Improved production of class I phosphatidylinositol 4,5-bisphosphate 3-kinase.

Phosphatidylinositol 4,5-bisphosphate 3-kinases (PI3K) are a family of kinases whose activity affects pathways needed for basic cell functions. As a result, PI3K is one of the most mutated genes in all human cancers and serves as an ideal therapeutic target for cancer treatment. Expanding on work done by other groups we improved protein yield to produce stable and pure protein using a variety of modifications including improved solubility tag, novel expression modalities, and optimized purification protocol and buffer. By these means, we achieved a 40-fold increase in yield for p110α/p85α and a 3-fold increase in p110α. We also used these protocols to produce comparable constructs of the ß and δ isoforms of PI3K. Increased yield enhanced the efficiency of our downstream high throughput drug discovery efforts on the PIK3 family of kinases.

Development and safety of investigational and approved drugs targeting the RAS function regulation in RAS mutant cancers.

The RAS gene family holds a central position in controlling key cellular activities such as migration, survival, metabolism, and other vital biological processes. The activation of RAS signaling cascades is instrumental in the development of various cancers. Although several RAS inhibitors have gained approval from the United States Food and Drug Administration (FDA) for their substantial antitumor effects, their widespread and severe adverse reactions significantly curtail their practical usage in the clinic. Thus, there exists a pressing need for a comprehensive understanding of these adverse events, ensuring the clinical safety of RAS inhibitors through the establishment of precise management guidelines, suitable intermittent dosing schedules, and innovative combination regimens. This review centers on the evolution of RAS inhibitors in cancer therapy, delving into the common adverse effects associated with these inhibitors, their underlying mechanisms, and the potential strategies for mitigation.

Association of various RAS codon mutations and prognostic outcomes of patients with colorectal liver metastases after hepatectomy.

PURPOSE: The prognostic and predictive value of RAS mutations in patients with colorectal liver metastases (CRLM) who have undergone hepatectomy holds substantial importance. The present study aimed to investigate the impact of different RAS codon mutations on long-term survival in CRLM patients. METHODS: A retrospective analysis was conducted on clinicopathological data from 399 CRLM patients with RAS mutations who underwent hepatectomy between January 2000 and December 2020. The RAS mutation gene status was assessed in KRAS codons (G12, G13, Q61, and A146) and NRAS codons (G12, G13, and Q61). Survival curves were generated using the Kaplan-Meier plotter and compared using the log-rank test. Univariate and multivariate analyses were performed to analyze the clinicopathological data. RESULTS: In the entire cohort, patients with KRAS G12 mutations exhibited the most favorable prognosis (p = 0.018). Comparatively, patients harboring KRAS Q61 mutations experienced poorer overall survival (OS) with a median of 15 months versus 33 months (p = 0.011) when compared to those with KRAS G12 mutations. Moreover, patients with NRAS Q61 mutations also showed decreased OS with a median of 26 months versus 33 months (p = 0.020) in comparison to KRAS G12 mutation patients. The results of multivariate analysis showed that both KRAS Q61 mutation (HR 2.130; 95% CI 1.088-4.168; p = 0.027) and NRAS Q61 mutation (HR 2.877; 95% CI 1.398-5.922; p = 0.004) were independent influencing factors of OS. Based on all identified risk factors, patients with RAS mutation were divided into high-risk and low-risk groups. Notably, in the high-risk group, the incorporation of postoperative chemotherapy was associated with longer OS, while it did not improve the survival of patients in the low-risk group. CONCLUSIONS: KRAS Q61 and NRAS Q61 mutations are promising predictors for OS in CRLM patients after hepatectomy. Postoperative chemotherapy may significantly benefit CRLM patients with RAS mutations, particularly those identified as high-risk.

Unresectable Ulcerative Colitis Associated Colon Cancer in a Young Japanese Patient: A Case Report.

We herein present the case of a 30-year-old Japanese male patient with ulcerative colitis (UC) who was admitted to our hospital because of significant ascites. Upon evaluation, the patient was diagnosed with unresectable UC-associated cancer (UCAC), localized in the transverse colon. Using gene profiling of the tumor tissue, anti-epidermal growth factor receptor (EGFR) antibody combination chemotherapy was selected. Subsequently, the patient exhibited a temporary response to this regimen, with an enhancement in his quality of life and he was able to survive for 12 months. This case underscores the potential benefits of aggressive chemotherapy tailored to the gene profile in UCAC treatment, offering insights into potential avenues for improving the patient prognosis.

A review and perspective paper: Ras oncogene gets modest, from kingpin to mere henchman.

The concomitant activation of both the YAP1 co-transcription factor and RAS GTPases is a hallmark of several aggressive cancers, though the intricacies of their relationship and implications for oncogenesis are still poorly understood. This review has presented a cooperative model where YAP1 and RAS are not independently acting oncogenes but rather interdependently acting ones, with each fulfilling an essential role within the oncogenic process. YAP1 is responsible for initiating the expression of key proteins that contribute to various cancer traits. However, these proteins must often be transported into the cytoplasm to exert their effects. We suggest that oncogenic RAS actually facilitates this transport, enabling the phosphorylation and subsequent activation of the nuclear transporter XPO1 (aka Exportin1). This mechanism is particularly crucial for anti-apoptotic proteins. Instead of being sequestered within the nucleus in an ineffective state, these proteins are rather shuttled into the cytoplasm. Within the cytoplasm, they can effectively inhibit apoptosis, undermining by these means the efficacy of chemotherapeutic agents designed to induce cell death in cancer cells. Therefore, a clearer understanding of the oncogenic partnership between RAS and YAP1 will likely provide new insights into the molecular underpinnings of cancer and highlight as well potential targets for therapeutic interventions designed to disrupt this pernicious interaction.

KRAS mutations detection methodology: from RFLP to CRISPR/Cas based methods.

In personalized cancer medicine, the identification of KRAS mutations is essential for making treatment decisions and improving patient outcomes. This work presents a comprehensive review of the current approaches for detection of KRAS mutations in different cancers. We highlight the value of fast and reliable KRAS mutations discovery and the effectiveness of molecular testing for selecting individuals who might benefit from targeted therapy. We provide an overview of various methods and tools available for detecting KRAS mutations, such as digital droplet PCR, next-generation sequencing (NGS), and polymerase chain reaction (PCR). We also address the difficulties and limitations in the identification of KRAS mutations, namely tumor heterogeneity and the emergence of resistance mechanisms. This article aims to guide clinicians in KRAS mutation identification.

Tolerance of Oncogene-Induced Replication Stress: A Fuel for Genomic Instability.

Activation of oncogenes disturbs a wide variety of cellular processes and induces physiological dysregulation of DNA replication, widely referred to as replication stress (RS). Oncogene-induced RS can cause replication forks to stall or collapse, thereby leading to DNA damage. While the DNA damage response (DDR) can provoke an anti-tumor barrier to prevent the development of cancer, a small subset of cells triggers replication stress tolerance (RST), allowing precancerous cells to survive, thereby promoting clonal expansion and genomic instability (GIN). Genomic instability (GIN) is a hallmark of cancer, driving genetic alterations ranging from nucleotide changes to aneuploidy. These alterations increase the probability of oncogenic events and create a heterogeneous cell population with an enhanced ability to evolve. This review explores how major oncogenes such as RAS, cyclin E, and MYC induce RS through diverse mechanisms. Additionally, we delve into the strategies employed by normal and cancer cells to tolerate RS and promote GIN. Understanding the intricate relationship between oncogene activation, RS, and GIN is crucial to better understand how cancer cells emerge and to develop potential cancer therapies that target these vulnerabilities.

An Analysis of Genetic Polymorphisms in 76 Genes Related to the Development of Ovarian Tumors of Different Aggressiveness.

Borderline ovarian tumors (BOTS) are rare neoplasms of intermediate aggressiveness between cystadenomas and low-grade ovarian cancers (lgOvCa), which they share some molecular resemblances with. In contrast to the most frequent and well-described high-grade ovarian carcinomas (hgOvCa), the molecular background of BOTS and lgOvCa is less thoroughly characterized. Here, we aimed to analyze genetic variants in crucial tumor suppressors and oncogenes in BOTS (with or without the BRAF V600E mutation), lgOvCa, and hgOvCa in two gene panels using next-generation sequencing. Then, we verified the existence of selected polymorphisms by Sanger sequencing. Finally, Western blot analyses were carried out to check the impact of the selected polymorphisms on the expression of the corresponding proteins. Our study contributes to the molecular characterization of ovarian neoplasms, demonstrating divergent polymorphic patterns pointing to distinct signaling pathways engaged in their development. Certain mutations seem to play an important role in BOTS without the BRAF V600E variant (KRAS) and in lgOvCa (KRAS and NRAS), but not in hgOvCa. Additionally, based on multivariable regression analyses, potential biomarkers in BOTS (PARP1) and hgOvCa (FANCI, BRCA2, TSC2, FANCF) were identified. Noteworthy, for some of the analyzed genes, such as FANCI, FANCD2, and FANCI, FANCF, TSC2, the status of BRCA1/2 and TP53, respectively, turned out to be crucial. Our results shed new light on the similarities and differences in the polymorphic patterns between ovarian tumors of diverse aggressiveness. Furthermore, the biomarkers identified herein are of potential use as predictors of the prognosis and/or response to therapy.

EMP1 knockdown mitigated high glucose-induced pyroptosis and oxidative stress in rat H9c2 cardiomyocytes by inhibiting the RAS/RAF/MAPK signaling pathway.

The purpose of this study was to investigate the mechanism of EMP1 action in high glucose (HG)-induced H9c2 cardiac cell pyroptosis and oxidative injury. Rat cardiomyocytes H9c2 were exposed to 33 mM glucose for 24, 48, or 72 h to induce cytotoxicity. EMP1-siRNA, NLRP3 agonist Nigericin, and pcNDA-RAS were used to treat H9c2 cells under HG conditions. Cell Counting Kit (CCK)-8 assay showed that cell proliferation was decreased following HG induction, which was rescued by EMP1 knockdown. Our results also suggested that EMP1 siRNA transfection significantly decreased the apoptosis and pyroptosis of HG-induced cells, as indicated by the reduction of NLRP3 IL-1ß, ASC, GSDMD, cleaved-caspase1 and cleaved-caspase3 levels in HG-induced H9c2 cells. In addition, EMP1 knockdown alleviated HG-induced mitochondrial damage and oxidative stress in H9c2 cells. NLRP3 activation reversed the inhibitory effects of EMP1 knockdown on pyroptosis and oxidative stress in HG-induced H9c2 cells. Mechanistically, we found that EMP1 knockdown suppressed the RAS/RAF/MAPK signaling pathway in HG-induced H9c2 cells. RAS overexpression blocked the protective effect of EMP1 knockdown on HG-induced H9c2 cell apoptosis, pyroptosis, and oxidative injury. Our findings suggest that EMP1 knockdown treatment might provide a novel therapy for diabetic cardiomyopathy.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and suicidality: A replication study using reports to the World Health Organization pharmacovigilance database (VigiBase®).

INTRODUCTION: Reports of suicidality associated with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been reported to the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA). We previously reported an increased reporting odds ratio (ROR) of some measures of suicidality with semaglutide and liraglutide using the FDA Adverse Event Reporting System (FAERS). Notwithstanding the increased ROR, causality between GLP-1 RAs exposure and any aspect of suicidality is not established. RESEARCH DESIGN AND METHODS: The analysis herein aims to extend a previous analysis of the FAERS by evaluating the ROR for suicidality reported to the World Health Organization (WHO) Pharmacovigilance Database (VigiBase). We aimed to characterize the ROR of suicidality associated with GLP-1 RAs, as extrapolated from spontaneous reports. As per our previous report, the ROR was considered significant when the lower limit of the 95 % confidence (CI) was >1.0. RESULTS: We searched VigiBase reports from inception to January 2024. The RORs for suicidal ideation were significantly increased for semaglutide (5.82), liraglutide (4.03) and tirzepatide (2.25). For "depression/suicidal", the ROR was significantly increased for semaglutide (14.74) and liraglutide (5.86); and for suicidal behaviour, the ROR was significantly increased for semaglutide (6.52) and liraglutide (3.90). However, for suicide attempts, the ROR was significantly decreased for semaglutide (0.11), dulaglutide (0.075), exenatide (0.047) and liraglutide (0.15). For completed suicide, the ROR was also significantly decreased for semaglutide (0.01), dulaglutide (0.003), exenatide (0.002) and liraglutide (0.008). CONCLUSION: Unlike our previous report with FAERS, a mixed pattern of ROR emerged in the WHO VigiBase with respect to suicidality and exposure to select GLP-RAs. Causation between GLP-1 RA exposure and suicidality (either increased or decreased) cannot be ascertained from ROR data.

Perioperative, functional, and oncological outcomes of Da Vinci vs. Hugo RAS for robot­assisted radical prostatectomy: evidence based on controlled studies.

A comparison was conducted between robot-assisted radical prostatectomy (RARP) performed using the Hugo RAS System and the Da Vinci System. We conducted an extensive search of online databases through September 2024. The data from eligible studies were pooled and analyzed with Review Manager 5.4, employing a random effects model. Weighted mean difference (WMD) and odds ratios (OR) with 95% confidence intervals (CI) were used to analyze continuous and categorical variables. A total of eight original studies, involving 1155 patients (HUGO-RARP: 468 vs. da Vinci-RARP: 687), were included. Compared with da Vinci-RARP, HUGO-RARP had a longer docking time (WMD: 6.2 min; 95% CI 4.25-8.14; p < 0.0001), while no significant differences were observed in total operative time, console time, bladder neck dissection time, seminal vesicle dissection time, vesicourethral anastomosis time, or pelvic lymph node dissection time between two systems. There were no significant differences in hospital stay, estimated blood loss, catheter duration, or complication rates. Likewise, oncological and functional outcomes were similar between the two systems. While these results suggest that the Hugo RAS system performs as well as the Da Vinci system in RARP, more randomized controlled studies are needed to further evaluate prognostic outcomes.

Unveiling new chapters in medullary thyroid carcinoma therapy: advances in molecular genetics and targeted treatment strategies.

Medullary Thyroid Carcinoma (MTC), a neuroendocrine malignancy that arises from the calcitonin-secreting parafollicular C-cells of the thyroid, constitutes a minor yet impactful fraction of thyroid malignancies. Distinguished by its propensity for aggressive growth and a pronounced tendency for metastasis, MTC poses formidable obstacles to the early diagnosis and therapeutic intervention. The molecular genetics of MTC, particularly the role of the RET gene and the RAS gene family, have been extensively studied, offering insights into the pathogenesis of the disease and revealing potential therapeutic targets. This comprehensive review synthesizes the latest advancements in the molecular genetics of MTC, the evolution of precision therapies, and the identification of novel biomarkers. We also discuss the implications of these findings for clinical practice and the future direction of MTC research.

Four-dimensional automated quantitative echocardiography assessment of right heart remodeling in patients with functional tricuspid regurgitation.

Background: Functional tricuspid regurgitation (FTR) has a pathophysiological connection with right heart remodeling. Given the increasing focus on right atrial remodeling in recent years, a comprehensive study of all aspects of right heart remodeling is crucial for understanding the progression and treatment of FTR. In the scientific literature, there is a lack of comprehensive exploration of right atrial remodeling in patients with FTR, and no reports on the potential correlation between the degree of this remodeling and the severity of tricuspid regurgitation (TR) have been published. This study aimed to evaluate the relationship between right heart parameters measured by four-dimensional (4D) automated quantitative echocardiography and the severity of TR in patients with FTR. Methods: In this prospective case-control study, 100 patients diagnosed with FTR by echocardiography at The First Affiliated Hospital of Guangxi Medical University from February 2022 to March 2023 were prospectively and consecutively selected as the case group, comprising 50 patients with mild FTR and 50 patients with moderate or severe FTR. Additionally, 30 healthy participants served as the control group. Routine echocardiography was employed to obtain two-dimensional (2D) and three-dimensional (3D) images, which was followed by 4D automated quantitative echocardiograph assessment. Analysis of variance (ANOVA) or Kruskal-Wallis tests were used to compare differences between groups, Pearson correlation coefficient analysis was used to discern the relationship between parameters and TR volume, multivariate linear regression was used to identify factors associated with TR volume, and logistic regression was employed to predict the severity of FTR. Results: The case group consisted of 50 patients with mild FTR (26 males, 52%; age range, 31-78 years; mean age ± SD: 58±11.4 years) and 50 patients with moderate-to-severe FTR (21 males, 42%; age range, 29-87 years; mean age ± SD: 60±13.0 years). Additionally, 30 healthy participants (13 males, 43%; age range, 19-81 years; mean age ± SD: 58±13.3 years) constituted the control group. Patients with moderate-to-severe FTR had significant right heart dilatation and functional decline. The TR volume was highly correlated with right atrium minimum volume (RAVmin; r=0.864; P<0.001), and linear regression showed that the RAVmin was independently correlated with the severity of TR in patients (ß=0.820; P<0.001). There were several predictive variables that were significantly associated with increased FTR severity, including right atrial reservoir strain [RASr; odds ratio (OR) =0.702; 95% confidence interval (CI): 0.575-0.857; P=0.001], right atrial conduit strain (RAScd; OR =1.308; 95% CI: 1.098-1.558; P=0.003), and right atrial reservoir circumferential strain (RASr-c; OR =0.823; 95% CI: 0.684-0.990; P=0.04). Conclusions: 4D automated quantitative echocardiography allows for the dynamic assessment of right heart volume and function. To determine the development of FTR, RA dilation appears to be more significant than right ventricular dilation. The RASr, RAScd, and RASr-c are directly correlated with FTR severity.

Characteristics and Prognosis of "Acute Promyelocytic Leukemia-like" Nucleophosmin-1-Mutated Acute Myeloid Leukemia in a Retrospective Patient Cohort.

Background: AML with NPM1 mutation is the largest subcategory of AML, representing about 35% of AML cases. It is characterized by CD34 negativity, which suggests a relatively differentiated state of the bulk of leukemic blasts. Notably, a significant subset of NPM1-mutated AML cases also exhibit HLA-DR negativity, classifying them as "double-negative", and mimicking, therefore, the CD34- HLA-DR- immunophenotype of acute promyelocytic leukemia (APL). Objectives: This study focuses on the "acute promyelocytic leukemia-like" ("APL-like") subset of NPM1-mutated AML, which can be challenging to distinguish from APL at presentation, prior to confirming RARa translocations. We aim to investigate the hematologic and immunophenotypic parameters that may aid to its distinction from APL. Additionally, we explore differences in genetic profile and prognosis between "APL-like" and "non-APL-like" NPM1-mutated AML cases. Methods: We conducted a retrospective evaluation of 77 NPM1-mutated AML cases and 28 APL cases. Results: Morphological characteristics, hematologic parameters (such as DD/WBC and PT/WBC), and specific immunophenotypic markers (including SSC, CD64, and CD4) can assist in the early distinction of "APL-like" NPM1-mutated AML from APL. Regarding differences in genetic profiles and outcomes between "APL-like" and non-"APL-like" NPM1-mutated AML cases, we observed a significantly higher incidence of IDH1/2 /TET2 mutations, along with a significantly lower incidence of DNMT3A mutations in the "APL-like" subset compared to the non-"APL-like" subset. The frequency of Ras-pathway and FLT3 mutations did not differ between these last two groups, nor did their prognoses. Conclusions: Our findings contribute to a comprehensive characterization of NPM1-mutated AML, enhancing diagnostic accuracy and aiding in the detailed classification of the disease. This information may potentially guide targeted therapies or differentiation-based treatment strategies.

Differences in Growth Performance and Meat Quality between Male and Female Juvenile Nile Tilapia (Oreochromis niloticus) during Separate Rearing.

This study compared the growth and flesh quality of juvenile male and female Nile tilapia grown in separate RAS tanks. The Genetic Sex Determination method yielded 40 males and 40 females. Males grew longer and heavier than females, and the results showed significant variation between the sexes in terms of weight gain rate (WGR), specific growth rate (SGR), and final body length and weight. In terms of the feed conversion ratio (FCR), Gonad Somatic Index (GSI), and Viscera Somatic Index (VSI), females presented better results than males. Male and female Hepatosomatic Index (HSI) values did not differ significantly-no difference in blood serum values. The meat's moisture and crude protein composition did not alter significantly from male to female; however, the crude fat and ash levels did differ significantly. Male and female animals were given the same seventeen distinct types of amino acids, and there was no distinct variation in the profiles of total amino acids (TAAs) and essential amino acids (EAAs) between the sexes. However, in the non-essential amino acid (NEAA) category, there were marginally significant differences, wherein females performed better than males. Males and females differed considerably in crude fat and ash levels but not in the moisture content or crude protein composition of the meat. Regarding fatty acids, males outperformed females in terms of total fatty acids (TFAs), polyunsaturated fatty acids (PUFAs), and saturated fatty acids (SFAs). However, no significant difference in the amount of monounsaturated fatty acids (MUFAs) in muscle was found between males and females.

First Worldwide Report of a Total Colectomy with the Hugo RAS Platform.

Background: Compared with the da Vinci platform, there is limited experience with the Hugo RAS® platform for colorectal surgery in Europe. This difference is especially notable when considering complex procedures such as total colectomy. Aim: To demonstrate the feasibility and safety of using the Hugo RAS® (Medtronic, Minneapolis, MN, USA) platform for total colectomy. Clinical case: An 18-year-old female patient with Familial Adenomatous Polyposis (FAP) and a BMI of 19 underwent a total colectomy with ileorectal anastomosis using the Hugo RAS® platform. The procedure lasted 253 min without complications. The postoperative period was uneventful, and she was discharged from the hospital on the third postoperative day. Conclusion: The Hugo RAS® platform is an emerging minimally invasive robotic that can be used even for total colectomy with proper patient selection. The placement and choice of arms and trocars were crucial to obtaining a similar operative time to the standard laparoscopic approach. The certification of Hugo's new instruments, such as energy devices and staplers, will make this platform even more competitive.

Atypical Exon 2/3 Mutants G48C, Q43K, and E37K Present Oncogenic Phenotypes Distinct from Characterized NRAS Variants.

NRAS belongs to the RAS family of GTPases. In colorectal cancer (CRC), NRAS mutations are rare compared to KRAS, but may lead to worse outcomes. We report the functional characterization of the novel NRAS mutants-G48C, Q43K, and E37K-identified in Filipino young-onset CRC patients. Unlike previously characterized NRAS mutants with no apparent effects on cell proliferation, these mutants enhanced proliferation of both HCT116 and NIH3T3 cells. This was confirmed in 3D spheroid assays to mimic the spatial organization of cells. G48C and E37K showed apoptosis resistance in both cell lines, and Q43K showed resistance in HCT116 cells. All three showed no effect on cellular migration in NIH3T3, but G48C enhanced the migration rate of HCT116 cells. Actin staining of NIH3T3 cells expressing the mutants showed a shrunken cytoplasm and transient structures associated with motility and invasiveness. Docking simulations show that GDP is only able to bind fully within the binding pocket of wild-type NRAS, but not in the mutants. Further, G48C, Q43K, and E37K all have less negative ΔG values, indicating a weaker GDP-binding affinity compared to wild-type NRAS. Taken together, the results suggest that oncogenic readouts of NRAS mutants are codon- and mutation-specific, with potential repercussions on the aggressiveness, resistance, and therapeutic response.

Robot-assisted Radical Prostatectomy with the Hugo RAS and da Vinci Surgical Robotic Systems: A Systematic Review and Meta-analysis of Comparative Studies.

BACKGROUND AND OBJECTIVE: The introduction of the Hugo RAS system represents a recent innovation in robotic surgery. The potential benefits and limitations of this system and its integration into clinical practice in urology have yet to be fully delineated. Our objective was to assess surgical, early oncological, and functional outcomes in studies comparing robot-assisted radical prostatectomy (RARP) performed with the new Hugo RAS system and the well-established da Vinci surgical system. METHODS: We conducted a systematic review and meta-analysis using PubMed, Web of Science, Scopus, and Embase databases. Eligible studies compared RARP outcomes in adult males between the Hugo RAS and da Vinci systems. The main endpoints were analyzed using a random-effects model, including perioperative outcomes (surgical times, estimated blood loss, length of hospital stay, Clavien-Dindo grade ≥2 complications), oncological outcomes (positive surgical margins and postoperative prostate-specific antigen), and functional outcomes (continence status and erectile function). KEY FINDINGS AND LIMITATIONS: Nine studies involving 1185 patients (478 Hugo RAS and 707 da Vinci) were included. Significant differences in pooled baseline characteristics included higher body mass index for the da Vinci cohort (p = 0.035) and a higher rate of palpable disease in the Hugo RAS cohort (p = 0.036). Docking time was significantly longer for the Hugo RAS, with a median difference of 6.1 min (95% confidence interval 3.9-8.2; I2 = 68.6%; p < 0.001; three studies). Overall, there were no significant differences in perioperative, oncological, and functional outcomes between the two systems. CONCLUSIONS AND CLINICAL IMPLICATIONS: Despite the preliminary nature of the evidence, this systematic review and meta-analysis show comparable surgical and clinical outcomes for RARP performed with the Hugo RAS system and the da Vinci robotic platform. PATIENT SUMMARY: We reviewed studies comparing the use of two different surgical robots for removal of the prostate. The results suggest that surgical and clinical outcomes with the new Hugo RAS robot are comparable to those with the established da Vinci robot for this procedure.

Acute freshwater CO2 exposure does not impair seawater transfer in three different sizes of Atlantic salmon (Salmo salar) subjected to different photoperiod manipulations.

There is a growing interest in Atlantic salmon (Salmo salar) aquaculture to extend the time fish are reared in freshwater (FW) recirculating aquaculture systems (RAS), producing larger FW salmon that can then be induced to undergo smoltification before transfer into marine net pens for grow-out and harvest. Smolts can be produced by photoperiod (PT) manipulation in RASs, but little is known about how delaying smoltification to larger body sizes affects susceptibility to elevated CO2 levels (hypercapnia), which can occur at high stocking densities in FW RAS or during transport from FW RAS rearing facilities to marine net pens. To address this, Atlantic salmon were reared from hatch to one of three different sizes (~230, ~580, or ~1300 g) in FW (3 ppt) under continuous light (24:0, light:dark). Once fish reached the desired sizes, a group of salmon were maintained on continuous light 24L:0D to serve as a control salmon. A second group of salmon were exposed to 8 weeks of 12L:12D and then to 4 weeks of 24L:0D to serve as PT treatment salmon, which is the PT manipulation commonly used in Atlantic salmon aquaculture to induce smoltification. At the end of PT manipulation, both control and PT treatment salmon were exposed to 0% or 1.5% CO2 (30 mg/L) for 96 h in FW and then transferred to air-equilibrated seawater (SW, 35 ppt, normocapnia). Salmon were sampled at the end of the 96-h FW CO2 exposure and at 24 h and 7 days in SW for measurements of blood ion/acid-base status, muscle water content (MWC), and gill and kidney Na+/K+ ATPase (NKA) activity. Exposure to 96 h of CO2 in FW resulted in acid-base disturbances in fish from all three size classes, with decreases in blood pH and increases in blood PCO2 and plasma [HCO3 -] but no mortality. Despite these large acid-base disturbances in FW, after transfer to normocapnic SW, there were no significant effects of CO2 exposure on extracellular blood pH, intracellular red blood cell pH, or plasma osmoregulatory status for all three sizes of post-smolt salmon. In general, SW transfer was associated with significant increases in plasma ions and osmolality, as well as gill and kidney NKA activity after 24 h and 1 week in SW with no significant impacts between different sizes of salmon. Thus, exposure to 30 mg CO2/L that mimics levels experienced during transport from FW RAS to an SW transfer site may have minimal effects on Atlantic salmon smolts up to 1300 g.

Successful cetuximab rechallenge in metastatic colorectal cancer: A case report.

BACKGROUND: Metastatic colorectal cancer (mCRC) treatment has been evolving and increasingly driven by tumor biology and gene expression analysis. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors (anti-EGFR) represents a promising strategy for patients with RAS wild-type (RAS-wt) mCRC and circulating tumor DNA has emerged as a potential selection strategy. Herein, we report the case of a RAS-wt mCRC patient who had a successful response to cetuximab rechallenge. CASE SUMMARY: Our patient was diagnosed with stage IV RAS-wt, microsatellite-stable rectosigmoid junction adenocarcinoma. He was started on first-line treatment with FOLFIRI and cetuximab and achieved partial response, allowing for a left hepatectomy (R0), followed by post-operative chemotherapy and an anterior resection; progression-free survival (PFS) of 16 months was obtained. Due to hepatic and nodal relapse, second-line treatment with FOLFOX and bevacizumab was started with partial response; metastasectomy was performed (R0), achieving a PFS of 11 months. After a 15 months anti-EGFR-free interval, FOLFIRI and cetuximab were reintroduced upon disease progression, again with partial response and a PFS of 16 months. Following extensive hepatic relapse, cetuximab was reintroduced and a marked clinical and analytical improvement was seen, after only one cycle. RAS-wt status was confirmed on circulating tumor DNA. The patient's overall survival exceeded 5 years. CONCLUSION: Our case provides real-world data to support cetuximab rechallenge in later lines of RAS-wt mCRC treatment.