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1.
bioRxiv ; 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38895202

ABSTRACT

URA3 is frequently used in the yeast community as the mutation target for 5-fluoroorotic acid (5-FOA) resistance. We identified a novel class of ura6 mutants that can grow in the presence of 5-FOA. Unlike ura3 mutants, ura6 mutants remain prototrophic and grow in the absence of uracil. In addition to 5-FOA resistance, we found that mutations to URA6 also confer resistance to 5-fluorocytosine (5-FC) and 5-fluorouracil (5-FU). In total, we identified 50 unique missense mutations across 32 residues of URA6 . We found that 28 out of the 32 affected residues are located in regions conserved between Saccharomyces cerevisiae and three clinically relevant pathogenic fungi. These findings suggest that mutations to URA6 present a second target for mutation screens utilizing 5-FOA as a selection marker as well as a potential mode of resistance to the antifungal therapeutic 5-FC.

2.
Org Lett ; 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38905202

ABSTRACT

Sequential oxidative cleavage and double-Mannich reactions enable the stereoselective conversion of simple norbornenes into complex alkaloid-like structures. The products undergo a wide range of derivatization reactions, including regioselective enol triflate formation/cross-coupling sequences and highly efficient conversion to an unusual tricyclic 8,5,5-fused lactam. Overall, the process represents a formal one-atom aza-ring expansion with concomitant bridging annulation, making it of interest for the broader derivatization of alkene feedstocks.

3.
RSC Adv ; 14(26): 18444-18452, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38860243

ABSTRACT

The family of radical-cation salts ß''-(BEDT-TTF)4[(A)M3+(C2O4)3]·guest (M = Fe, Cr, Ga, Al, Co, Mn, Rh, Ru; A = K+, H3O+, NH4 +) has produced superconductors, metals, semiconductors, and metal-insulators through introduction of different guest molecules into the structure. We present three new additions to the family ß''-(BEDT-TTF)4[(A)Cr(C2O4)3]·guest with the guest molecules toluene, phenol, or salicylaldehyde. These new guests are liquid or solid additives within the electrocrystallisation medium. All three salts show metallic behaviour from room temperature down to <10 K and do not show a superconducting transition.

4.
Semin Radiat Oncol ; 34(3): 276-283, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38880536

ABSTRACT

Spatially fractionated radiotherapy (SFRT) includes historical grid therapy approaches but more recently encompasses the controlled introduction of one or more cold dose regions using intensity modulation delivery techniques. The driving hypothesis behind SFRT is that it may allow for an increased immune response that is otherwise suppressed by radiation effects. With both two- and three-dimensional SFRT approaches, SFRT dose distributions typically include multiple dose cold spots or valleys. Despite its unconventional methods, reported clinical experience shows that SFRT can sometimes induce marked tumor regressions, even in patients with large hypoxic tumors. Preclinical models using extreme dose distributions (i.e., half-sparing) have been shown to nevertheless result in full tumor eradications, a more robust immune response, and systemic anti-tumor immunity. SFRT takes advantage of the complementary immunomodulatory features of low- and high-dose radiotherapy to integrate the delivery of both into a single target. Clinical trials using three-dimensional SFRT (i.e., lattice-like dose distributions) have reported both promising tumor and toxicity results, and ongoing clinical trials are investigating synergy between SFRT and immunotherapies.


Subject(s)
Dose Fractionation, Radiation , Immunotherapy , Neoplasms , Humans , Immunotherapy/methods , Neoplasms/radiotherapy , Neoplasms/immunology
5.
medRxiv ; 2024 May 31.
Article in English | MEDLINE | ID: mdl-38854002

ABSTRACT

Introduction: Cryptococcal meningitis remains a prominent cause of death in persons with advanced HIV disease. CSF leukocyte infiltration predicts survival at 18 weeks; however, how CSF immune response relates to CSF leukocyte infiltration is unknown. Methods: We enrolled 401 adults with HIV-associated cryptococcal meningitis in Uganda who received amphotericin and fluconazole induction therapy. We assessed the association of CSF leukocytes, chemokine, and cytokine responses with 18-week survival. Results: Participants with CSF leukocytes ≥50/µL, had higher probability 68% (52/77) of 18-week survival compared with 52% (151/292) 18-week survival in those with ≤50 cells/µL (Hazard Ratio=1.63, 95% confidence intervals 1.14-2.23; p=0.008). Survival was also associated with higher expression of T helper (Th)-1, Th17 cytokines, and immune regulatory elements. CSF levels of Programmed Death-1 Ligand, CXCL10, and Interleukin (IL)-2 independently predicted survival. In multivariate analysis, CSF leukocytes were inversely associated with CSF fungal burden and positively associated with CSF protein, interferon-gamma (IFN-γ), IL-17A, tumor necrosis factor (TNF)-α, and peripheral blood CD4+ and CD8+ T cells expression. Conclusion: 18-week survival after diagnosis of cryptococcal meningitis was associated with higher CSF leukocytes at baseline with greater T helper 1 (IFN-γ, IL-2 and TNF-α cytokines), T helper 17 (IL-17A cytokine) and CXCR3+ T cell (CXCL10 chemokine) responses. These results highlight the interdependent contribution of soluble and cellular immune responses in predicting survival with HIV-associated cryptococcal meningitis.

7.
Commun Earth Environ ; 5(1): 290, 2024.
Article in English | MEDLINE | ID: mdl-38826489

ABSTRACT

High northern latitude changes with Arctic amplification across a latitudinal forest gradient suggest a shift towards an increased presence of trees and shrubs. The persistence of change may depend on the future scenarios of climate and on the current state, and site history, of forest structure. Here, we explore the persistence of a gradient-based shift in the boreal by connecting current forest patterns to recent tree cover trends and future modeled estimates of canopy height through 2100. Results show variation in the predicted potential height changes across the structural gradient from the boreal forest through the taiga-tundra ecotone. Positive potential changes in height are concentrated in transitional forests, where recent positive changes in cover prevail, while potential change in boreal forest is highly variable. Results are consistent across climate scenarios, revealing a persistent biome shift through 2100 in North America concentrated in transitional landscapes regardless of climate scenario.

8.
Surg Endosc ; 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38877318

ABSTRACT

INTRODUCTION: Improving surgical access in low- and middle-income countries is vital for the 5 billion people who lack safe surgical care. Tailoring a culturally sensitive approach to consent is essential for patient comprehension and comfort, thereby alleviating the effects of resource constraints and advancing equitable care. This study examines the consenting process for endoscopy at Kyabirwa Surgical Center in Kyabirwa, Jinja, Uganda, to assess patients' knowledge and attitudes as a potential barrier to participating in endoscopic procedures. METHODS: All adult upper endoscopy (EGD) and colonoscopy patients were recruited to participate in a survey of their demographics, knowledge, and attitudes toward their procedure. All patients received a standard consultation explaining the procedure and its risks and benefits. RESULTS: 75 patients were included; median age was 54 years and 56% (n = 42) were women. 92% (n = 69) of patients had never had an endoscopy before and 73% (n = 55) of patients were scheduled for an EGD while the remaining 27% (n = 20) were scheduled for a colonoscopy. Most patients 80% (n = 60) had a basic understanding of what an endoscopy is and 87% (n = 65) its diagnostic purpose. Few patients 15% (n = 11) knew of the most common side effects or if they would have a surgical scar 27% (n = 20). Overall, 46.7% (n = 35) of patients were moderately or severely fearful of getting an endoscopy. Additionally, 45.3% (n = 34) of patients were moderately or severely fearful of receiving anesthesia during their endoscopic procedure. Despite this fear, most patients 85.3% (n = 64) stated that they understood the benefits of the procedure either very well or extremely well. CONCLUSIONS: Most patients understood the role that an endoscopic procedure plays in their care and its potential benefits. Despite this, many patients continued to have high levels of fear associated with both the endoscopic procedure and with receiving anesthesia during their procedure. Future patient education should focus on addressing patients' fears and the risks of undergoing an endoscopy, which may improve the utilization of surgical services.

9.
JBJS Rev ; 12(5)2024 May 01.
Article in English | MEDLINE | ID: mdl-38768282

ABSTRACT

BACKGROUND: Total humerus replacement (THR) is a reconstruction procedure performed after resection of massive humeral tumors. However, there is limited literature on the rates of failure and functional outcomes of this implant. Our study aimed to determine the main failure modes, implant survival, and postoperative functional outcomes of THR. METHODS: A comprehensive search of the PubMed and Embase databases was conducted. We registered our study on PROSPERO (448684) and used the Strengthening the Reporting of Observational Studies in Epidemiology checklist for quality assessment. The Henderson classification was used to assess endoprosthesis failure and the Musculoskeletal Tumor Society (MSTS) score for functional outcomes. Weighted means and standard deviations were calculated. RESULTS: Ten studies comprising 171 patients undergoing THR were finally included. The overall failure rate was 32.2%. Tumor progression (12.6%) and prosthetic infections (9.4%) were the most common failure modes, followed by soft-tissue failures (5.9%), aseptic loosening (3.5%), and structural failure (1.8%). Two-year, 5-year, and 10-year implant survival rates for the entire cohort were 86%, 81%, and 69.3%. Ten-year implant survival for primary THRs was 78.3%, compared with 38.6% for revision THRs (p = 0.049). The mean MSTS score at the last follow-up was 77%. Patients whose implants did not fail had a higher MSTS score (79.3%) than those with failed implants (71.4%) (p = 0.02). CONCLUSION: One-third of THR will fail, mostly due to tumor progression and prosthetic infection. Overall functional scores were acceptable, with MSTS scores displaying great hand and elbow function but limited shoulder function. LEVEL OF EVIDENCE: Level III. See Instructions for Authors for a complete description of levels of evidence.


Subject(s)
Bone Neoplasms , Humerus , Humans , Humerus/surgery , Bone Neoplasms/surgery , Treatment Outcome , Male , Plastic Surgery Procedures/methods , Female
10.
J Surg Oncol ; 2024 May 27.
Article in English | MEDLINE | ID: mdl-38798273

ABSTRACT

BACKGROUND: Vacuum-assisted closure (VAC) temporization is a technique associated with high local control rates used in myxofibrosarcoma. We sought to compare the costs and postoperative outcomes of VAC temporization and single-stage (SS) excision/reconstruction. METHODS: We conducted a retrospective analysis of patients with myxofibrosarcoma surgically treated at our institution between 2000 and 2022. Variables of interest included total, direct, and indirect costs for initial episode of care, 90 days and 1 year after initial admission, and postoperative outcomes. Costs were compared between the VAC temporization and SS groups. RESULTS: After matching, 13 patients in the SS group and 23 in the VAC group were analyzed. We found no difference in median and mean total inpatient costs, between the VAC temporization and SS group. While total 90-day and 1-year costs were higher in the VAC group compared to the SS group, mean costs were similar. There were no differences in postoperative complications between groups. A subanalysis of the entire cohort (n = 139) revealed lower local recurrence and overall death rates in the VAC temporization group. CONCLUSION: VAC temporization had similar inpatient costs and postoperative outcomes to SS excision/reconstruction. While median 90-day and 1-year costs were higher in the VAC group, mean costs did not differ.

11.
SAGE Open Med ; 12: 20503121241241922, 2024.
Article in English | MEDLINE | ID: mdl-38751571

ABSTRACT

Objective: This study aimed to find a potential association between the DRD2 Taq1A gene polymorphism (rs1800497 C32806T) and personality traits. Methods: In all, 249 youths were recruited for this study. The Short-form Revised Eysenck Personality Questionnaire was administered to assess personality traits. The participants were genotyped for the DRD2 Taq1A polymorphism using the polymerase chain reaction-restriction fragment length polymorphism method. Statistical analysis was carried out to find a possible association between the genotypes and aspects of personality traits assessed. Results: The frequencies of the A1 and A2 alleles in our sampled population were 215 (43.2%) and 283 (56.8%), while the frequencies of A1A1, A1A2, and A2A2 were 67 (26.9%), 81 (32.5%), and 101 (40.6%), respectively. The study population was not in Hardy-Weinberg equilibrium (χ2 = 17.64, p < 0.001). The A2 allele was significantly associated with extraversion. Although this allele was also associated with neuroticism, psychoticism, and lie, the association was not significant. Conclusion: The A2 allele of the DRD2 Taq1A polymorphism was found to be more associated with extraversion, as measured by the Short-form Revised Eysenck Personality Questionnaire.

12.
Ecol Evol ; 14(5): e11390, 2024 May.
Article in English | MEDLINE | ID: mdl-38770129

ABSTRACT

Ten state wildlife management agencies in the United States, including six within the Southeast, have delayed their spring wild turkey (Meleagris gallopavo) hunting seasons since 2017 by five or more days to address concerns related to the potential effects of hunting on wild turkey seasonal productivity. One hypothesis posits that if the spring hunting season is too early, there may be insufficient time for males to breed hens before being harvested, thus leading to reduced seasonal productivity. We conducted an experiment to determine whether delaying the wild turkey hunting season by 2 weeks in south-middle Tennessee would affect various reproductive rates. In 2021 and 2022, the Tennessee Fish and Wildlife Commission experimentally delayed the spring hunting season to open 14 days later than the traditional date (the Saturday closest to 1 April) in Giles, Lawrence, and Wayne counties. We monitored reproductive rates from 2017 to 2022 in these three counties as well as two adjacent counties, Bedford and Maury, that were not delayed. We used a Before-After-Control-Impact design to analyze the proportion of hens nesting, clutch size, hatchability, nest success, poult survival and hen survival with linear mixed-effect models and AIC model selection to detect relationships between the 14-day delay and reproductive parameters. We detected no relationship (p > .05) between the 14-day delay and any individual reproductive parameter. In addition, recruitment (hen poults per hen that survived until the next breeding season) was very low (<0.5) and did not increase because of the 14-day delay. The traditional Tennessee start date had been in place since 1986 while the turkey harvest increased markedly until about 2006 and more recently stabilized. Our data indicate that moving the start of the hunting season from a period just prior to peak nest initiation to 2 weeks later, to coincide with a period just prior to peak nest incubation initiation, resulted in no change to productivity or populations in wild turkey flocks in south-middle Tennessee.

13.
Article in English | MEDLINE | ID: mdl-38773833

ABSTRACT

BACKGROUND: Stem fixation in reconstruction after resection of femoral tumors is debated. Cemented stems offer immediate stability but risk aseptic loosening, while press-fit stems allow bone ingrowth but risk stress shielding and subsidence. Our retrospective review aimed to determine implant failure rates and their associated factors, as well as the rates of infection, debridement, and mortality for both fixation groups (cemented or press-fit stems) used in patients undergoing resection of femoral tumor disease and subsequent arthroplasty. METHODS: We retrospectively studied 252 patients who underwent resection of femoral tumors and subsequent arthroplasty using cemented (n = 173; 69%) or press-fit (noncemented) (n = 79; 31%) stems between 1999 and 2020. Implant failure was the primary outcome, with secondary outcomes including rates of implant infection, debridement, and mortality. Multivariable regression was done to assess risk factors for implant failures. RESULTS: The study found implant failure rates of 11% and 18% for cemented stems and press-fit stems, respectively. Lower stem to diaphyseal ratios (P = 0.024) and younger patients (P = 0.008) were associated with a higher risk of implant failure in cemented stems. The infection rates were 14% and 10% for cemented and press-fit stems, respectively. Debridement rates were 16% and 13% for cemented and press-fit stems, respectively, while the 1-year mortality rate was 16% for cemented stems and 1.5% for press-fit stems. CONCLUSIONS: This study is the largest of its kind, providing patient characteristics and outcomes in both cemented and press-fit stems in the setting of reconstruction for femoral tumors. Both methods can be effective, with outcomes dependent on patient-specific factors, such as life expectancy, activity level, and body habitus, as well as proper implant fit. Additional studies of both implants and longer follow-up are required to elucidate the optimal fixation method for each individual patient. LEVEL OF EVIDENCE: Level III, retrospective noncomparative study.

14.
J Nematol ; 56(1): 20240016, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38737093

ABSTRACT

Nematodes play a vital ecological role in soil and marine ecosystems, but there is limited information about their dietary diversity and feeding habits. Due to methodological challenges, the available information is based on inference rather than confirmed observations. The lack of correct dietary requirements also hampers rearing experiments. To achieve insight into the prey of mononchid nematodes, this study employed high-throughput Illumina paired-end sequencing using universal eukaryotic species 18S primers on 10 pooled mononchid nematode species, namely Mylonchulus brachyuris, M. brevicaudatus, Mylonchulus sp., Clarkus parvus, Prionchulus sp. M. hawaiiensis, M. sigmaturellus, M. vulvapapillatus, Anatonchus sp. and Miconchus sp. The results indicate that mononchids are associated with a remarkable diversity of eukaryotes, including fungi, algae, and protists. While the metabarcoding approach, first introduced here for mononchids, proved to be a simple and rapid method, it has several limitations and crucial methodological challenges that should be addressed in future studies. Ultimately, such methods should be able to evaluate the dietary complexity of nematodes and provide a valuable avenue for unraveling the dietary requirements of previously unculturable nematodes. This can contribute to the methodology of understanding their feeding habits and contributions to ecosystem dynamics.

15.
Subst Abuse Treat Prev Policy ; 19(1): 25, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38702783

ABSTRACT

BACKGROUND: There is little study of lifetime trauma exposure among individuals engaged in medication treatment for opioid use disorder (MOUD). A multisite study provided the opportunity to examine the prevalence of lifetime trauma and differences by gender, PTSD status, and chronic pain. METHODS: A cross-sectional study examined baseline data from participants (N = 303) enrolled in a randomized controlled trial of a mind-body intervention as an adjunct to MOUD. All participants were stabilized on MOUD. Measures included the Trauma Life Events Questionnaire (TLEQ), the Brief Pain Inventory (BPI), and the Posttraumatic Stress Disorder Checklist (PCL-5). Analyses involved descriptive statistics, independent sample t-tests, and linear and logistic regression. RESULTS: Participants were self-identified as women (n = 157), men (n = 144), and non-binary (n = 2). Fifty-seven percent (n = 172) self-reported chronic pain, and 41% (n = 124) scored above the screening cut-off for PTSD. Women reported significantly more intimate partner violence (85%) vs 73%) and adult sexual assault (57% vs 13%), while men reported more physical assault (81% vs 61%) and witnessing trauma (66% vs 48%). Men and women experienced substantial childhood physical abuse, witnessed intimate partner violence as children, and reported an equivalent exposure to accidents as adults. The number of traumatic events predicted PTSD symptom severity and PTSD diagnostic status. Participants with chronic pain, compared to those without chronic pain, had significantly more traumatic events in childhood (85% vs 75%). CONCLUSION: The study found a high prevalence of lifetime trauma among people in MOUD. Results highlight the need for comprehensive assessment and mental health services to address trauma among those in MOUD treatment. TRIAL REGISTRATION: NCT04082637.


Subject(s)
Chronic Pain , Opioid-Related Disorders , Stress Disorders, Post-Traumatic , Humans , Stress Disorders, Post-Traumatic/epidemiology , Stress Disorders, Post-Traumatic/drug therapy , Chronic Pain/drug therapy , Chronic Pain/epidemiology , Female , Male , Cross-Sectional Studies , Adult , Opioid-Related Disorders/drug therapy , Opioid-Related Disorders/epidemiology , Sex Factors , Middle Aged , Psychological Trauma/epidemiology
16.
Acta Parasitol ; 69(2): 1244-1252, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38705947

ABSTRACT

PURPOSE: Artemisinin combination therapies, the first-line antimalarials in Nigeria, have reportedly suffered multiple failures in malaria treatment, hence the search for novel combination of other compounds. Methyl gallate and palmatine have been reported to exhibit antiplasmodial activities but the antimalarial activity of their combination has not been evaluated. Therefore, the evaluation of the combination of methyl gallate and palmatine for antimalarial activity in vitro and in vivo in the presence of piperine was carried out. MATERIALS AND METHODS: The inhibitory potential of methyl gallate and palmatine combination on ß-hematin (hemozoin) formation was studied in vitro. Also, the antimalarial activity of methyl gallate and palmatine combination with/without a bioenhancer (piperine) was evaluated in Plasmodium berghei NK65-infected mice. RESULTS: Methyl gallate and palmatine in the ratio 3:2 acted synergistically in vitro and had the highest inhibitory effect (IC50 = 0.73 µg/mL) on ß-hematin (hemozoin) formation. The 3:2 combination of methyl gallate and palmatine exhibited no antimalarial activity in vivo in the absence of piperine but caused reduction in parasitemia that exceeded 40% in the presence of piperine at the dose of 25 mg/kg body weight on days 6 and 8 post-inoculation in mice. CONCLUSION: The 3:2 combination of methyl gallate and palmatine in the presence of piperine exhibited antimalarial activity in vivo, possibly by synergistic inhibition of hemozoin formation which may cause accumulation of haem within the food vacuole of Plasmodium spp. and its death.


Subject(s)
Alkaloids , Antimalarials , Benzodioxoles , Berberine Alkaloids , Drug Synergism , Gallic Acid , Malaria , Piperidines , Plasmodium berghei , Polyunsaturated Alkamides , Animals , Polyunsaturated Alkamides/pharmacology , Antimalarials/pharmacology , Benzodioxoles/pharmacology , Piperidines/pharmacology , Malaria/drug therapy , Malaria/parasitology , Mice , Gallic Acid/pharmacology , Gallic Acid/analogs & derivatives , Alkaloids/pharmacology , Plasmodium berghei/drug effects , Berberine Alkaloids/pharmacology , Parasitemia/drug therapy , Inhibitory Concentration 50 , Hemeproteins
17.
Radiother Oncol ; 196: 110320, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38740091

ABSTRACT

BACKGROUND AND PURPOSE: Radiation pneumonitis (RP) is a common side effect of thoracic radiotherapy and often has a long course characterized by acute exacerbations and progression to permanent lung fibrosis. There are no validated biomarkers of prognosis in patients diagnosed with RP. MATERIALS AND METHODS: We analyzed a time course of serum chemokines, cytokines, and other proteins from patients with grade 2+ RP in a randomized clinical trial of a steroid taper plus nintedanib, a multiple tyrosine kinase inhibitor, versus placebo plus a steroid taper for the treatment of RP. Weighted gene correlation network analysis (WGCNA) and univariable zero inflated Poisson models were used to identify groups of correlated analytes and their associations with clinical outcomes. RESULTS: Thirty enrolled patients had biomarker data available, and 17 patients had enough analytes tested for network analysis. WGNCA identified ten analytes, including transforming growth factor beta-1 (TGF-ß1), monocyte chemoattractant protein-1 (MCP-1), and platelet-derived growth factor (PDGF), that in aggregate were correlated with the occurrence of pulmonary exacerbations (p = 0.008), the total number of acute pulmonary exacerbations (p = 0.002), and treatment arm (p = 0.036). By univariable analysis, an increase in rate of change of two components of the RP module were associated with an increased incidence rate of pulmonary exacerbations: interleukin 5 (IL-5, incidence rate ratio (IRR) 1.02, 95% CI 1.01-1.04, p = 0.002), and tumor necrosis factor superfamily 12 (TNFSF12, IRR 1.06, CI 1-1.11, p = 0.036). An increased slope of epidermal growth factor (EGF) was associated with a decreased incidence rate of exacerbations (IRR 0.94, CI 0.89-1, p = 0.036). CONCLUSION: We identified a panel of serum biomarkers that showed association with nintedanib treatment and acute pulmonary exacerbations in patients with RP. A confirmatory study will be needed to validate this panel for use as a prognostic tool in patients with RP.


Subject(s)
Biomarkers , Indoles , Radiation Pneumonitis , Humans , Radiation Pneumonitis/etiology , Radiation Pneumonitis/blood , Male , Indoles/therapeutic use , Female , Biomarkers/blood , Aged , Middle Aged , Lung Neoplasms/radiotherapy , Lung Neoplasms/drug therapy , Disease Progression
18.
Clin Cancer Res ; 2024 May 22.
Article in English | MEDLINE | ID: mdl-38775859

ABSTRACT

PURPOSE: The genetic intratumoral heterogeneity observed in human osteosarcomas (OS) poses challenges for drug development and the study of cell fate, plasticity, and differentiation, processes linked to tumor grade, cell metastasis, and survival. EXPERIMENTAL DESIGN: To pinpoint errors in OS differentiation, we transcriptionally profiled 31,527 cells from a tissue-engineered model that directsMSCs toward adipogenic and osteoblastic fates. Incorporating pre-existing chondrocyte data, we applied trajectory analysis and non-negative matrix factorization (NMF) to generate the first human mesenchymal differentiation atlas. RESULTS: This 'roadmap' served as a reference to delineate the cellular composition of morphologically complex OS tumors and quantify each cell's lineage commitment. Projecting a bulk RNA-seq OS dataset onto this roadmap unveiled a correlation between a stem-like transcriptomic phenotype and poorer survival outcomes. CONCLUSIONS: Our study quantifies OS differentiation and lineage, a prerequisite to better understanding lineage-specific differentiation bottlenecks that might someday be targeted therapeutically.

19.
Acta Radiol Open ; 13(5): 20584601241252335, 2024 May.
Article in English | MEDLINE | ID: mdl-38737559

ABSTRACT

Background: Uterine cavity pathology may affect the endometrium or myometrium, resulting in distortion of the uterine cavity, and is responsible for 2%-5% of infertility. The methods for its assessment usually involve imaging modalities like pelvic ultrasonography, often transvaginal-(TVS), and hysterosalpingography-(HSG), with hysteroscopy-(HSC) as the gold standard. However, HSC is not readily available in resource-poor-settings. Purpose: To determine and compare the diagnostic accuracy of TVS and HSG in detecting uterine cavity pathology using HSC as a gold standard. Materials and Methods: A cross-sectional analytical study of consenting infertile women for evaluation of the uterine cavity using transvaginal-ultrasonography, hysterosalpingogram, and hysteroscopy. The primary-outcome-measures were the sensitivity, specificity, and accuracy of TVS and HSG in detecting uterine cavity abnormalities using HSG as the gold standard. Results: Eighty-eight participants were analysed for this study. The lesions confirmed on HSC were intrauterine-adhesions (43.1%), endometrial polyps (14.8%), submucous fibroids (18.2%), intrauterine-septum (13.6%), and cavity distortion (14.8%). The overall sensitivity with TVS was 57.7%, with a specificity of 97.6%, a positive-predictive-value (PPV) of 88.2%, and a negative-predictive-value (NPV) of 88.2%, giving a percentage-accuracy of 88.2%. In comparison, HSG had a sensitivity of 72.1%, a specificity of 99.4%, a PPV of 97.4%, and an NPV of 92.0%, giving an overall accuracy of 92.9%. The detection rates of TVS and HSG in this category were: fibroids (97.7% vs 89.8%; p = .0004) and adhesions (73.9% vs 87.5%; p = .0002), respectively. Conclusion: HSG appears to be the superior modality for detection of obliterative uterine cavity pathologies, while TVS is better suited for myometrium and endometrial lesions.

20.
APMIS ; 2024 May 13.
Article in English | MEDLINE | ID: mdl-38741286

ABSTRACT

Myositis ossificans, a benign tumor composed of spindle cells and osteoblasts, can clinically and radiologically mimic osteosarcoma. While recognition and accurate diagnosis of myositis ossificans can be a challenge, this is critical as it may allow a conservative surgical approach to maximize functional outcomes. Herein, we present a patient with surface myositis ossificans confirmed genetically by the presence of COL1A1::USP6 gene fusion, along with a literature review. Due to the enhanced visualization of the bone matrix, computed tomography (CT) imaging may be a superior imaging modality to magnetic resonance (MR) imaging. Staged biopsies with samples obtained from the periphery and center of the lesions may allow pathologists to discern the zonal distribution histologically. Furthermore, immunohistochemistry fluorescence in situ hybridization and molecular testing can aid in the distinction of myositis ossificans from mimics. Because of their resemblance to other bone tumors, these cases of myositis ossificans highlight the importance of a multidisciplinary approach integrating clinical, radiologic, and pathologic analysis and involving serial imaging, sampling, and judicious use of ancillary immunohistochemical and molecular testing.

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