Complete Laparoscopic Type C2 Radical Surgery for Cervical Stump Cancer: No-Look and No-Touch Techniques.

BACKGROUND: Due to previous surgical history and subsequent adhesions between pelvic organs, surgery for cervical stump cancer (CSC) is technically more challenging than surgery for cervical cancer with an intact uterus.1 We aimed to illustrate the related anatomy, surgical steps and techniques of complete laparoscopic type C2 radical surgery (CLRS) for early-stage CSC. METHODS: CLRS for six patients with CSC was performed from January 2021 to January 2022. We demonstrated the detailed skills of parametrial management during CLRS for CSC in case 5 by means of a video. A 58-year-old woman diagnosed with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IIA1 CSC received CLRS through five operative ports (Fig. 1). RESULTS: The magnetic resonance imaging (MRI) scans and gross appearance of the specimen are shown in Fig. 2. The median age and body mass index (BMI) of the six patients were 53 years and 23.8, respectively. The median blood loss was 275 mL; the median time of operation was 218 min; the median length of hospitalization was 15 days; and the median time to recover urinary function was 12 days. One patient underwent postoperative radiation for pathologically proven adenocarcinoma with deep stromal invasion,2 while the other five did not. After a median follow-up of 24 months, no patients experienced complications, recurrence, or death (Table 1). CONCLUSIONS: This study details the skills of CLRS for CSC, especially space development and the 'no-look, no-touch' tumor-free principle. It is helpful for clinicians to perform safe and standardized surgery on patients with early-stage CSC. Fig. 1 Trocar placement of complete laparoscopic type C2 radical surgery for early-stage CSC. CSC cervical stump cancer, S superior, I inferior, R right, L left, U umbilicus Fig. 2 MRI scans and gross appearance of the specimen for case 5 with CSC at FIGO 2018 stage IIA1. The tumor lesion on the cervical stump is indicated by yellow arrows. a Axial T2-weighted image; b DKI image; c ADC map; d sagittal T2-weighted image; e sagittal T1-weighted image; f gross appearance of the surgical specimen. MRI magnetic resonance imaging, CSC cervical stump cancer, FIGO International Federation of Gynecology and Obstetrics, DKI diffusional kurtosis imaging, ADC apparent diffusion coefficient Table 1 Clinicopathological characteristics, operative details, and outcomes of patients with cervical stump cancer Patient no. Age at diagnosis (years) BMI Reasons for subtotal hysterectomy FIGO 2018 stage Histology Operation Operation time (mins) Blood loss (mL) Urinary catheter (days) Hospital stay (days) Complications Depth of invasion LVSI LNs dissected TNM stage Tumor size (mm) Postoperative radiotherapy Follow-up (months) Recurrence Death 1 50 25.9 Uterine myoma IIA1 ASC CLRS+PLND 221 360 10 12 No Middle one-third N 13 T2a1N0M0 16 No 30 No No 2 55 17.3 Uterine myoma IB1 AC CLRS+PLND 191 270 20 12 No Deep one-third N 24 T1b1N0M0 10 Yes 20 No No 3 50 24.8 Uterine myoma IB1 SC CLRS+PLND 295 310 13 15 No Superficial one-third N 21 T1b1N0M0 15 No 25 No No 4 63 30.1 Uterine myoma IB1 SC CLRS+PLND 213 180 6 16 No Superficial one-third N 25 T1b1N0M0 15 No 19 No No 5 58 20.2 Postpartum hemorrhage IIA1 SC CLRS+PLND 220 100 11 14 No Middle one-third N 21 T2a1N0M0 15 No 24 No No 6 46 22.7 Uterine myoma IB1 SC CLRS+PLND 215 120 14 17 No Superficial one-third N 26 T1b1N0M0 12 No 23 No No BMI body mass index, FIGO International Federation of Gynecology and Obstetrics, ASC cervical adenosquamous carcinoma, AC cervical adenocarcinoma, SC cervical squamous carcinoma, CLRS+PLND complete laparoscopic radical surgery and pelvic node dissections, LVSI lymphovascular space invasion, N negative, LNs lymph nodes, TNM tumor node metastasis.

Dual chemodynamic/photothermal therapeutic nanoplatform based on DNA-functionalized prussian blue.

The combination of chemodynamic therapy and photothermal therapy has a promising application owing to its impressive anti-cancer effects. However, the degradability of the material and the lack of targeting severely limit its further clinical application. Herein, DNAs containing nucleolin aptamer (AS1411) and different bases sequences were used to functionalize PB NPs for the targeted treatment. Compared to prussian blue, DNA-functionalized prussian blue does not reduce the photothermal properties of prussian blue. Moreover, DNA confers DNA-functionalized prussian blue targeting and higher enzymatic activity, thereby achieving a more effective combination of chemodynamic and photothermal treatment. The therapeutic efficacy of this nanoplatform was evaluated in vivo and in vitro experiments, exhibiting that DNA-functionalized prussian blue nanozyme can maximize the precise control of the therapeutic effect, reduce the toxic and side effects caused by non-specific accumulation on other normal cells, and effectively achieve targeted killing of cancer cells. This work demonstrates that DNA-functionalized prussian blue can improve the efficiency of combined tumor treatment and enhance the application value of prussian blue in tumor treatment, which is expected to provide theoretical support for clinical application.

Topotecan clearance based on a single sample and a population pharmacokinetic model: Application to a pediatric high-risk neuroblastoma clinical trial.

BACKGROUND: Topotecan, an antitumor drug with systemic exposure (SE)-dependent activity against many pediatric tumors has wide interpatient pharmacokinetic variability, making it challenging to attain the desired topotecan SE. The study objectives were to update our topotecan population pharmacokinetic model, to evaluate the feasibility of determining individual topotecan clearance using a single blood sample, and to apply this approach to topotecan data from a neuroblastoma trial to explore exposure-response relationships. PROCEDURE: Our previous population pharmacokinetic and covariate model was updated using data from 13 clinical pediatric studies. A simulation-based Bayesian analysis was performed to determine if a single blood sample could be sufficient to estimate individual topotecan clearance. Following the Bayesian approach, single pharmacokinetic samples collected from a Children's Oncology Group Phase III clinical trial (ANBL0532; NCT0056767) were analyzed to estimate individual topotecan SE. Associations between topotecan SE and toxicity or early response were then evaluated. RESULTS: The updated population model included the impact of patient body surface area (BSA), age, and renal function on topotecan clearance. The Bayesian analysis with the updated model and single plasma samples showed that individual topotecan clearance values were estimated with good precision (mean absolute prediction error ≤16.2%) and low bias (mean prediction error ≤7.2%). Using the same approach, topotecan SE was derived in patients from ANBL0532. The exposure-response analysis showed an increased early response after concomitant cyclophosphamide and topotecan up to a topotecan SE of 45 h ng/mL. CONCLUSIONS: A simple single-sample approach during topotecan therapy could guide dosing for patients, resulting in more patients reaching target attainment.

64-channel label-free fluorescence detection and single-particle counting device.

A 64-channel detection system for laser-induced fluorescence (LIF) detection at the cell level is established and applied to single event counting. Generally, fluorescence detection at the cellular level requires a dyeing label to enhance the scattered light intensity for the photodetector. However, the dyeing labels, such as fluorophores, probes, and dyes, complicate sample preparation and increase cytotoxicity in the process. Therefore, label-free detection becomes essential for in vivo research. The presented 64-channel detection system is designed for label-free detection with the ability to record feeble emissions. Two linear photodetector devices are included in the system, extending the wavelength detection range to 366-680 nm with an improved spectral resolution at an average of 4.9 nm. The performance of the system was validated by detecting unlabeled human hepatocytes (L-02) and other cell-level biologic samples. In addition, the 64-channel detection system was also used for particle counting with a quartz microfluidic chip. The counting method is based on fluorescence spectra differs from those of other devices (i.e., flow cytometry and cell-sorting equipment), which use isolated irradiance intensities.

Improved KS-GMM algorithm applied in classification and recognition of honey based on laser-induced fluorescence spectra.

The laser-induced fluorescence (LIF) technique, which has been widely used for food testing, can be combined with various algorithms to classify and recognize different kinds of honey. This paper proposes the Kolmogorov-Smirnov test-Gaussian mixture model (KS-GMM) algorithm, which is coupled with the LIF technique to realize accurate classification and recognition of different types of pure honey. The experiments are designed and carried out to obtain a set of LIF spectrum data from various honey and syrup samples. The proposed KS-GMM algorithm is applied for classification and recognition, with GMM, k-nearest neighbor (kNN), and decision tree algorithms as cross-validation methods. By comparing recognition results of training sets containing different amounts of data, it is found that the KS-GMM algorithm exhibits a maximum recognition accuracy of 96.52%. The research results prove that the KS-GMM algorithm outperforms, to the best of our knowledge, the other three algorithms in classifying and recognizing the honey types.

The 3D Modeling System for Bioaerosol Distribution Based on Planar Laser-Induced Fluorescence.

Although it is quite challenging to image and analyze the spatial distribution of bioaerosols in a confined space, a three-dimensional (3D) modeling system based on the planar laser-induced fluorescence (PLIF) technique is proposed in this paper, which is designed to analyze the temporal and spatial variations of bioaerosol particles in a confined chamber. The system employs a continuous planar laser source to excite the fluoresce, and a scientific complementary metal oxide semiconductor (sCMOS) camera to capture images of 2048 × 2048 pixels at a frame rate of 12 Hz. While a sliding platform is moving back and forth on the track, a set of images are captured at different positions for 3D reconstruction. In this system, the 3D reconstruction is limited to a maximum measurement volume of about 50 cm × 29.7 cm × 42 cm, with a spatial resolution of about 0.58 mm × 0.82 mm × 8.33 mm, and a temporal resolution of 5 s. Experiments were carried out to detect the PLIF signals from fluorescein aerosols in the chamber, and then 3D reconstruction was used to visualize and analyze the diffusion of aerosol particles. The results prove that the system can be applied to clearly reconstruct the 3D distribution and record the diffusion process of aerosol particles in a confined space.

Dual-channel mobile fluorescence lidar system for detection of tryptophan.

We present a dual-channel mobile lidar system based on laser-induced fluorescence (LIF) for real-time standoff detection and concentration distribution analysis of tryptophan. The system employs an ultraviolet laser excitation source and signal detectors for receiving fluorescence signals within two different wavelength bands. The performed experiments measured tryptophan aerosols at two different standoff distances. Moreover, distilled water and ethanol solutions were also detected for comparison. The results show that the system can detect LIF signals of tryptophan, give early warnings, locate the diffusion sources, and monitor the variation of the aerosol concentration distribution in real time.

An electrochemical dual-signaling aptasensor for the ultrasensitive detection of insulin.

Insulin plays a central role in physiological glycolmetabolism and is associated with diabetes and related diseases. In this work, a dual-signaling electrochemical aptasensor for insulin detection with high sensitivity and specificity has been reported. Methylene blue (MB)-modified insulin-binding aptamer (IBA) as "signal-off" probe, and (DNA2)/Ferrocene (Fc) co-modified gold nanoparticles (DNA2Fc@GNPs) as the "signal-on" probe were integrated with linker mDNA to fabricate the DNA2Fc@GNPs/mDNA/MB-IBA modified Au electrode as the sensing interface, and the current responses of MB and Fc were used as signal indicators. As expected, the incubation of insulin with DNA2Fc@GNPs/mDNA/MB-IBA/Au electrode resulted in the current responses of MB and Fc decreased and increased, respectively. Based on this strategy, the detection of insulin was successfully achieved, and a linear range from 10 pM to 10 nM with the detectable lowest concentration of 0.1 pM was obtained. By measuring the insulin concentrations in serum samples, this proposed aptasensor has been proven to be of high specificity and accuracy. Moreover, the dual-signaling is useful for the more accurate and reproducible detection through their self-referencing capability. This aptasensor possesses such advantages as simplicity, rapid responses, high sensitivity, specificity and accuracy, which is significant for improving the diagnosis of insulin-related diseases.

Prognostic Value of Metabolic and Volumetric Parameters of FDG PET in Pediatric Osteosarcoma: A Hypothesis-generating Study.

Purpose To preliminarily assess the potential prognostic value of various fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) parameters before, during, and after neoadjuvant chemotherapy (NCT). Materials and Methods Thirty-four patients with osteosarcoma were enrolled prospectively from 2008 to 2012 and underwent FDG PET/computed tomography (CT) imaging before (baseline scan), during (interim scan) and after NCT (posttherapy scan). The study was approved by the institutional review board and informed consent was received from patients. Maximum and peak standardized uptake value (SUVmax and SUVpeak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured. Predictive value of FDG PET parameters for event-free survival (EFS) and overall survival (OS) were evaluated. Multivariable Cox regression analysis for EFS and OS was performed by using histologic response and initial presence of metastasis as covariates. Results At baseline scan, SUVpeak, MTV, and TLG were predictive of EFS (P = .006-.03) and OS (P = .001-.03) but not associated with histologic response. At interim and posttherapy scan, SUVmax, SUVpeak, MTV, and TLG were associated with histologic response (P = .0002-.04) and predictive of EFS (P = .004-.02) and OS (P = .001-.03). Multivariable Cox regression analysis revealed that the FDG PET parameters either at baseline, interim, or posttherapy were independently predictive of EFS and OS. In particular, baseline MTV was an independent predictor of EFS (hazard ratio, 5.0 [95% confidence interval {CI}: 1.5, 16.8]) and OS (hazard ratio, 29.4 [95% CI: 2.2, 392.2]). Conclusion SUVpeak, MTV, and TLG either at baseline, interim, or posttherapy were predictive of EFS and OS and may be useful prognostic biomarkers for osteosarcoma. © RSNA, 2018 Online supplemental material is available for this article.

Prospective study of neuropathic pain after definitive surgery for extremity osteosarcoma in a pediatric population.

BACKGROUND: Neuropathic pain (NP) after definitive surgery for extremity osteosarcoma (OS) has not been previously characterized. This study prospectively investigates the incidence, duration, and treatment of NP in limb sparing surgery and amputation groups. PROCEDURE: In patients treated for OS on a chemotherapy and definitive surgery (limb sparing vs. amputation) protocol (OS08), we prospectively collected the following data: (i) demographical data (age, sex, race); (ii) NP time of onset and duration; and (iii) dose (starting, maximum) and duration of gabapentin, amitriptyline, and methadone treatment. RESULTS: Thirty-seven patients underwent 38 definitive surgeries: limb sparing (26, 68.4%) or amputations (12, 31.6%). Localization included lower extremity (30, 81%), upper extremity (6, 16%), or pelvis (1, 3%). Thirty patients (81%) developed NP and 26 of them required NP-specific medications (87.7%). The mean [standard deviation (SD)] duration of NP was 6.5 weeks (7.2) (median 4.4, range 0.3-29.9). All 26 patients (27 surgeries) treated with NP medications received gabapentin, either as single therapy (65.4%) (17 patients, 18 surgeries), dual therapy with gabapentin and amitriptyline (five patients), or triple therapy with gabapentin, amitriptyline, and methadone (four patients). The mean starting (maximum) doses of gabapentin, amitriptyline, and methadone (mg/kg/day) were 20.2 (43.8), 0.5 (0.7), and 0.3 (0.3), respectively. The incidence and duration of NP, duration of treatment, and NP-specific dose regimens were similar in the limb sparing and the amputation groups. CONCLUSIONS: NP after definitive surgery for OS is frequently encountered, can persist for a significant time, and NP outcomes are similar in limb sparing and amputation groups.

Influence of bony resection margins and surgicopathological factors on outcomes in limb-sparing surgery for extremity osteosarcoma.

BACKGROUND: Limb-sparing surgery for osteosarcoma requires taking wide bony resection margins while maximizing preservation of native bone and joint. However, the optimal bony margin and factors associated with recurrence and survival outcomes in these patients are not well established. PROCEDURE: We conducted a retrospective review of outcomes in children and adolescents with newly diagnosed osteosarcoma from 1986 to 2012, where bony resection margins for limb-sparing surgeries were decreased serially from 5 to 1.5 cm. The association between bony margins and other surgicopathological factors with survival and recurrence outcomes was determined. RESULTS: In 181 limb-sparing surgeries in 173 patients, planned and actual bony resection margins were not significantly associated with local recurrence-free survival (LRFS), event-free survival (EFS), and overall survival (OS)-at median 5.8 years follow-up, decreasing planned bony resection margins from 5 to 1.5 cm did not significantly decrease survival outcomes. Multivariable analysis showed that the presence of distant metastases at diagnosis was associated with decreased LRFS, EFS, and OS (P = 0.002, 0.005, and <0.0001, respectively). Post-chemotherapy tumor necrosis ≤90% was associated with decreased EFS and OS (P = 0.001 and 0.022, respectively). Earlier years of treatment and pathologic fractures were associated with decreased OS only (P = 0.018 and 0.008, respectively); previous cancer history and male gender were associated with decreased EFS only (P = 0.043 and 0.023, respectively). CONCLUSION: We did not observe significant increase in adverse survival outcomes with reduction of longitudinal bony resection margins to 1.5 cm. Established prognostic factors, particularly histologic response to chemotherapy and metastases at diagnosis, remain relevant in limb-sparing patients. Pediatr Blood Cancer 2015;62:246-251. © 2014 Wiley Periodicals, Inc.

A systematic review on global zoonotic virus-associated mortality events in marine mammals.

Marine mammals play a critical role as sentinels for tracking the spread of zoonotic diseases, with viruses being the primary causative factor behind infectious disease induced mortality events. A systematic review was conducted to document marine mammal mortality events attributed to zoonotic viral infections in published literature across the globe. This rigorous search strategy yielded 2883 studies with 88 meeting inclusion criteria. The studies spanned from 1989 to 2023, with a peak in publications observed in 2020. Most of the included studies were retrospective, providing valuable insights into historical trends. The United States (U.S.) reported the highest number of mortality events followed by Spain, Italy, Brazil and the United Kingdom. Harbor seals were the most impacted species, particularly in regions like Anholt, Denmark and the New England Coast, U.S. Analysis revealed six main viruses responsible for mortality events, with Morbillivirus causing the highest proportion of deaths. Notably, the occurrence of these viral events varied geographically, with distinct patterns observed in different regions. Immunohistochemistry emerged as the most employed detection method. This study underscores the importance of global surveillance efforts in understanding and mitigating the impact of viral infections on marine mammal populations, thereby emphasizing the necessity of collaborative One Health approaches to address emerging threats at the human-animal-environment interface. Additionally, the potential transfer of zoonotic viruses to aquatic organisms used in food production, such as fish and shellfish, highlights the broader implications for food safety, food security and public health.

Analysis of Prognostic Factors and Cancer-Specific Survival in Patients with Undifferentiated and Dedifferentiated Endometrial Carcinoma Undergoing Various Postoperative Adjuvant Therapies.

Purpose: To investigate prognostic factors affecting cancer-specific survival (CSS) and to analyze the survival outcomes of patients with undifferentiated and dedifferentiated endometrial carcinoma (UDEC) who underwent various postoperative adjuvant therapies. Methods: The independent risk factors affecting CSS were studied using univariate and multivariate Cox regression analysis, and CSS in the presence of various postoperative treatments was evaluated using Kaplan-Meier method based on the cohort with pathologically confirmed UDEC from the Surveillance, Epidemiology, and End Results (SEER) database. Meanwhile, the study included 18 cases with UDEC in our center and explored their molecular characteristics and prognosis. Results: Between 2000 and 2019, a total of 443 patients were included from the SEER database. The median CSS duration was 14 months, with corresponding 3- and 5-year CSS rates of 45.9% and 44.0%, respectively. Factors such as pTNM stage, surgical resection of primary lesion, and chemoradiation independently influenced CSS. Postoperative chemotherapy alone improved CSS in patients with initial tumor spread beyond the uterus (pT3 and pT4), or lymph node (LN) invasion, or distant metastases. Additionally, postoperative radiotherapy enhanced CSS in patients who had undergone postoperative chemotherapy, those with primary tumors progressing to stage pT3, and those with LN involvement but without distant metastases. Of the 18 patients diagnosed at our center, with a median follow-up of 15.5 months, one experienced relapse and two succumbed to UDEC, who exhibited aberrant p53 expression in immunohistochemical staining. Conclusion: Postoperative chemotherapy and radiotherapy are beneficial for UDEC patients with tumors extending beyond the uterus or involving lymph nodes.

Pharmacogenomics, Race, and Treatment Outcome in Pediatric Acute Myeloid Leukemia.

Importance: Disparities in outcomes exist between Black and White patients with acute myeloid leukemia (AML), with Black patients experiencing poorer prognosis compared with their White counterparts. Objective: To assess whether varying intensity of induction therapy to treat pediatric AML is associated with reduced disparities in treatment outcome by race. Design, Setting, and Participants: A comparative effectiveness analysis was conducted of 86 Black and 359 White patients with newly diagnosed AML who were enrolled in the AML02 trial from 2002 to 2008 or the AML08 trial from 2008 to 2017. Statistical analysis was conducted from July 2023 through January 2024. Interventions: Patients in AML02 were randomly assigned to receive standard low-dose cytarabine-based induction therapy or augmented high-dose cytarabine-based induction therapy, whereas patients in AML08 received high-dose cytarabine-based therapy. Main Outcomes and Measures: Cytarabine pharmacogenomic 10-single-nucleotide variant (ACS10) scores were evaluated for association with outcome according to race and treatment arm. Results: This analysis included 86 Black patients (mean [SD] age, 8.8 [6.5] years; 54 boys [62.8%]; mean [SD] leukocyte count, 52 600 [74 000] cells/µL) and 359 White patients (mean [SD] age, 9.1 [6.2] years; 189 boys [52.6%]; mean [SD] leukocyte count, 54 500 [91 800] cells/µL); 70 individuals with other or unknown racial and ethnic backgrounds were not included. Among all patients without core binding factor AML who received standard induction therapy, Black patients had significantly worse outcomes compared with White patients (5-year event-free survival rate, 25% [95% CI, 9%-67%] compared with 56% [95% CI, 46%-70%]; P = .03). By contrast, among all patients who received augmented induction therapy, there were no differences in outcome according to race (5-year event-free survival rate, Black patients, 50% [95% CI, 38%-67%]; White patients, 48% [95% CI, 42%-55%]; P = .78). Among patients who received standard induction therapy, those with low ACS10 scores had a significantly worse 5-year event-free survival rate compared with those with high scores (42.4% [95% CI, 25.6%-59.3%] and 70.0% [95% CI, 56.6%-83.1%]; P = .004); however, among patients who received augmented induction therapy, there were no differences in 5-year event-free survival rates according to ACS10 score (low score, 60.6% [95% CI, 50.9%-70.2%] and high score, 54.8% [95% CI, 47.1%-62.5%]; P = .43). Conclusions and Relevance: In this comparative effectiveness study of pediatric patients with AML treated in 2 consecutive clinical trials, Black patients had worse outcomes compared with White patients after treatment with standard induction therapy, but this disparity was eliminated by treatment with augmented induction therapy. When accounting for ACS10 scores, no outcome disparities were seen between Black and White patients. Our results suggest that using pharmacogenomics parameters to tailor induction regimens for both Black and White patients may narrow the racial disparity gap in patients with AML.

Pharmacogenomic Score Effectively Personalizes Treatment of Acute Myeloid Leukemia.

PURPOSE: Cytarabine (also known as ara-C) has been the backbone of acute myeloid leukemia (AML) chemotherapy for more than five decades. Recent pharmacogenomics-based 10-SNP ara-C (ACS10) scores showed low ACS10 (≤0) to be associated with poor outcomes in patients with AML treated with standard chemotherapy. Here, we evaluated the ACS10 score in the context of three different induction I regimens in patients with pediatric AML. EXPERIMENTAL DESIGN: ACS10 score groups (low, ≤0, or high, >0) were evaluated for association with event-free survival (EFS) and overall survival (OS) by three randomized treatment arms in patients treated on the AML02 (NCT00136084) and AML08 (NCT00703820) clinical trials: AML02 low-dose ara-C (LDAC arm, n = 91), AML02 + AML08 high-dose ara-C (HDAC arm, n = 194), and AML08 clofarabine + ara-C (Clo/ara-C arm, n = 105) induction I regimens. RESULTS: Within the low-ACS10 score (≤0) group, significantly improved EFS and OS were observed among patients treated with Clo/ara-C as compared with LDAC (EFS, HR = 0.45; 95% CI, 0.23-0.88; P = 0.020; OS, HR = 0.44; 95% CI, 0.19-0.99; P = 0.048). In contrast, within the high-ACS10 score group (score >0), augmentation with Clo/ara-C was not favorable as compared with LDAC (Clo/ara-C vs. LDAC, EFS, HR = 1.95; 95% CI, 1.05-3.63; P = 0.035; OS, HR = 2.10; 95% CI, 0.96-4.59; P = 0.063). Personalization models predicted 9% improvement in the outcome in ACS10 score-based tailored induction (Clo/ara-C for low and LDAC for high-ACS10 score groups) as compared with nonpersonalized approaches (P < 0.002). CONCLUSIONS: Our findings suggest that tailoring induction regimens using ACS10 scores can significantly improve outcomes in patients with AML. Given the SNPs are germline, preemptive genotyping can accelerate matching the most effective remission induction regimen.

Integrated drug resistance and leukemic stemness gene-expression scores predict outcomes in large cohort of over 3500 AML patients from 10 trials.

In this study, we leveraged machine-learning tools by evaluating expression of genes of pharmacological relevance to standard-AML chemotherapy (ara-C/daunorubicin/etoposide) in a discovery-cohort of pediatric AML patients (N = 163; NCT00136084 ) and defined a 5-gene-drug resistance score (ADE-RS5) that was predictive of outcome (high MRD1 positivity p = 0.013; lower EFS p < 0.0001 and OS p < 0.0001). ADE-RS5 was integrated with a previously defined leukemic-stemness signature (pLSC6) to classify patients into four groups. ADE-RS5, pLSC6 and integrated-score was evaluated for association with outcome in one of the largest assembly of ~3600 AML patients from 10 independent cohorts (1861 pediatric and 1773 adult AML). Patients with high ADE-RS5 had poor outcome in validation cohorts and the previously reported pLSC6 maintained strong significant association in all validation cohorts. For pLSC6/ADE-RS5-integrated-score analysis, using Group-1 (low-scores for ADE-RS5 and pLSC6) as reference, Group-4 (high-scores for ADE-RS5 and pLSC6) showed worst outcome (EFS: p < 0.0001 and OS: p < 0.0001). Groups-2/3 (one high and one low-score) showed intermediate outcome (p < 0.001). Integrated score groups remained an independent predictor of outcome in multivariable-analysis after adjusting for established prognostic factors (EFS: Group 2 vs. 1, HR = 4.68, p < 0.001, Group 3 vs. 1, HR = 3.22, p = 0.01, and Group 4 vs. 1, HR = 7.26, p < 0.001). These results highlight the significant prognostic value of transcriptomics-based scores capturing disease aggressiveness through pLSC6 and drug resistance via ADE-RS5. The pLSC6 stemness score is a significant predictor of outcome and associates with high-risk group features, the ADE-RS5 drug resistance score adds further value, reflecting the clinical utility of simultaneous testing of both for optimizing treatment strategies.

Somatic mitochondrial DNA mutations are a source of heterogeneity among primary leukemic cells.

Somatic mitochondrial DNA (mtDNA) mutations are prevalent in tumors, yet defining their biological significance remains challenging due to the intricate interplay between selective pressure, heteroplasmy, and cell state. Utilizing bulk whole-genome sequencing data from matched tumor and normal samples from two cohorts of pediatric cancer patients, we uncover differences in the accumulation of synonymous and nonsynonymous mtDNA mutations in pediatric leukemias, indicating distinct selective pressures. By integrating single-cell sequencing (SCS) with mathematical modeling and network-based systems biology approaches, we identify a correlation between the extent of cell-state changes associated with tumor-enriched mtDNA mutations and the selective pressures shaping their distribution among individual leukemic cells. Our findings also reveal an association between specific heteroplasmic mtDNA mutations and cellular responses that may contribute to functional heterogeneity among leukemic cells and influence their fitness. This study highlights the potential of SCS strategies for distinguishing between pathogenic and passenger somatic mtDNA mutations in cancer.

Study on power coupling of annular vortex beam propagating through a two-Cassegrain-telescope optical system in turbulent atmosphere.

As a new attractive application of the vortex beams, power coupling of annular vortex beam propagating through a two- Cassegrain-telescope optical system in turbulent atmosphere has been investigated. A typical model of annular vortex beam propagating through a two-Cassegrain-telescope optical system is established, the general analytical expression of vortex beams with limited apertures and the analytical formulas for the average intensity distribution at the receiver plane are derived. Under the H-V 5/7 turbulence model, the average intensity distribution at the receiver plane and power coupling efficiency of the optical system are numerically calculated, and the influences of the optical topological charge, the laser wavelength, the propagation path and the receiver apertures on the power coupling efficiency are analyzed. These studies reveal that the average intensity distribution at the receiver plane presents a central dark hollow profile, which is suitable for power coupling by the Cassegrain telescope receiver. In the optical system with optimized parameters, power coupling efficiency can keep in high values with the increase of the propagation distance. Under the atmospheric turbulent conditions, great advantages of vortex beam in power coupling of the two-Cassegrain-telescope optical system are shown in comparison with beam without vortex.

Temporal and spatial relationships of CrAssphage and enteric viral and bacterial pathogens in wastewater in North Carolina.

Enteric disease remains one of the most common concerns for public health, particularly when it results from human exposure to surface and recreational waters contaminated with wastewater. Characterizing the temporal and spatial variation of enteric pathogens prevalent in wastewater is critical to develop approaches to mitigate their distribution in the environment. In this study, we aim to characterize pathogen variability and test the applicability of the human-associated wastewater indicator crAssphage as an indicator of enteric viral and bacterial pathogens. We conducted weekly samplings for 14 months from four wastewater treatment plants in North Carolina, USA. Untreated wastewater samples were processed using hollow fiber ultrafiltration, followed by secondary concentration methods. Adenovirus, norovirus, enterovirus, Salmonella, Shiga toxin 2 (stx2), Campylobacter, and crAssphage were measured by quantitative polymerase chain reaction (qPCR) and reverse transcriptase (rt)-qPCR. Our results revealed significant correlations between crAssphage and human adenovirus, enterovirus, norovirus, Salmonella, and Campylobacter (p<0.01). Pathogens and crAssphage concentrations in untreated wastewater showed distinct seasonal patterns, with peak concentrations of crAssphage and viral pathogens in fall and winter, while bacterial pathogens showed peaked concentrations in either winter (Campylobacter), fall (Salmonella), or summer (stx2). This study enhances the understanding of crAssphage as an alternative molecular indicator for both bacterial and viral pathogens. The findings of this study can also inform microbial modeling efforts for the prediction of the impact of wastewater pathogens on surface waters due to increased flooding events and wastewater overflows associated with climate change.

SAMHD1 single nucleotide polymorphisms impact outcome in children with newly diagnosed acute myeloid leukemia.

Cytarabine arabinoside (Ara-C) has been the cornerstone of acute myeloid leukemia (AML) chemotherapy for decades. After cellular uptake, it is phosphorylated into its active triphosphate form (Ara-CTP), which primarily exerts its cytotoxic effects by inhibiting DNA synthesis in proliferating cells. Interpatient variation in the enzymes involved in the Ara-C metabolic pathway has been shown to affect intracellular abundance of Ara-CTP and, thus, its therapeutic benefit. Recently, SAMHD1 (SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1) has emerged to play a role in Ara-CTP inactivation, development of drug resistance, and, consequently, clinical response in AML. Despite this, the impact of genetic variations in SAMHD1 on outcome in AML has not been investigated in depth. In this study, we evaluated 25 single nucleotide polymorphisms (SNPs) within the SAMHD1 gene for association with clinical outcome in 400 pediatric patients with newly diagnosed AML from 2 clinical trials, AML02 and AML08. Three SNPs, rs1291128, rs1291141, and rs7265241 located in the 3' region of SAMHD1 were significantly associated with at least 1 clinical outcome: minimal residual disease after induction I, event-free survival (EFS), or overall survival (OS) in the 2 cohorts. In an independent cohort of patients from the COG-AAML1031 trial (n = 854), rs7265241 A>G remained significantly associated with EFS and OS. In multivariable analysis, all the SNPs remained independent predictors of clinical outcome. These results highlight the relevance of the SAMHD1 pharmacogenomics in context of response to Ara-C in AML and warrants the need for further validation in expanded patient cohorts.