Epigenomic and transcriptomic profiling of solitary fibrous tumors identifies site-specific patterns and candidate genes regulated by DNA methylation.

Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm which can arise at any anatomic site and is characterized by recurrent NAB2::STAT6 fusions and metastatic progression in 10-30%. The cell of origin has not been identified. Despite some progress in understanding the contribution of heterogeneous fusion types and secondary mutations to SFT biology, epigenetic alterations in extrameningeal SFT remain largely unexplored, and most sarcoma research to date has focused on the use of methylation profiling for tumor classification. We interrogated genome-wide DNA methylation in 79 SFTs to identify informative epigenetic changes. RNA-seq data from targeted panels and data from the Cancer Genome Atlas (TCGA) were used for orthogonal validation of selected findings. In unsupervised clustering analysis, the top 500 most variable CpGs segregated SFTs by primary anatomic site. Differentially methylated genes (DMGs) associated with primary SFT site included EGFR, TBX15, multiple HOX genes and their cofactors EBF1, EBF3, and PBX1, as well as RUNX1 and MEIS1. Of the 20 DMGs that were interrogated on the RNA-seq panel, twelve were significantly differentially expressed according to site. However, with the exception of TBX15, most of these also showed differential expression according to NAB2::STAT6 fusion type, suggesting that the fusion oncogene contributes to transcriptional regulation of these genes. Transcriptomic data confirmed an inverse correlation between gene methylation and the expression of TBX15 in both SFT and TCGA sarcomas. TBX15 also showed differential mRNA expression and 5' UTR methylation between tumors located in different anatomic sites in TCGA data. In all analyses, TBX15 methylation and mRNA expression retained the strongest association with tissue of origin in SFT and other sarcomas, suggesting a possible marker to distinguish metastatic tumors from new primaries without genomic profiling. Epigenetic signatures may further help to identify SFT progenitor cells at different anatomic sites.

Financial incentives to increase engagement across the hepatitis C care cascade among people at risk of or diagnosed with hepatitis C: A systematic review.

BACKGROUND: Reversing declining rates of people initiating and completing hepatitis C (HCV) treatment, observed in many countries, is needed to achieve global HCV elimination goals. Providing financial incentives to increase HCV testing and treatment uptake among people at-risk of or living with HCV infection could be an effective intervention. We conducted a systematic review to assess evidence regarding the effectiveness of financial incentives to improve engagement and progression through the HCV care cascade. METHODS: We searched MEDLINE, PubMed and EMBASE for studies published from January 2013 to January 2023 that evaluated financial incentives offered to people living with and at-risk of HCV to increase HCV antibody and or RNA testing, linkage to care, treatment initiation, treatment adherence, treatment completion, and sustained viral load (SVR) testing. Open-label randomised controlled trials (RCTs), controlled non-randomised studies, cohort or observation studies and mixed-methods studies were included, whereas literature reviews, case series and studies which did not report data were excluded. RESULTS: We identified 1,278 studies, with 21 included after full-text screening (14,913 participants); three randomised controlled trials and 18 non-randomised studies. Studies evaluated incentives aimed at improving test uptake (n = 11), engagement in care (n = 13), treatment initiation (n = 8), adherence (n = 3), completion (n = 3) and attainment of SVR (n = 5). Findings provided inconclusive evidence for the effectiveness of incentives in improving engagement in the HCV cascade of care. Determining incentive effectiveness to improve care cascade engagement was limited by low quality study designs, heterogeneity in type (cash or voucher), value (US$5 to $600) and cascade stage being incentivised. No randomised controlled trials assessed the effectiveness of incentives to promote HCV testing, and none showed an impact on treatment uptake. In non-randomised studies (observational comparative), some evidence suggested that incentives promoted HCV testing, but evidence of their role in promoting linkage to care, HCV treatment adherence and treatment completion were mixed. CONCLUSION: Currently, there lacks high-quality evidence evaluating whether financial incentives improve HCV testing and treatment outcomes. Future research should seek to standardise methodologies, compare incentive types and values to enhance engagement in HCV care, and determine factors that support incentives effectiveness.

Impact of PIK3CA gain and PTEN loss on mantle cell lymphoma biology and sensitivity to targeted therapies.

ABSTRACT: Besides many other mutations in known cancer driver genes, mantle cell lymphoma (MCL) is characterized by recurrent genetic alterations of important regulators of the phosphoinositol-3-kinase (PI3K) cascade including PIK3CA gains and PTEN losses. To evaluate the biological and functional consequences of these aberrations in MCL, we have introduced transgenic expression of PIK3CA (PIK3CA UP) and performed knockout/knockdown of PTEN gene (PTEN KO/KD) in 5 MCL cell lines. The modified cell lines were tested for associated phenotypes including dependence on upstream B-cell receptor (BCR) signaling (by an additional BCR knockout). PIK3CA overexpression decreased the dependence of the tested MCL on prosurvival signaling from BCR, decreased levels of oxidative phosphorylation, and increased resistance to 2-deoxy-glucose, a glycolysis inhibitor. Unchanged protein kinase B (AKT) phosphorylation status and unchanged sensitivity to a battery of PI3K inhibitors suggested that PIK3CA gain might affect MCL cells in AKT-independent manner. PTEN KO was associated with a more distinct phenotype: AKT hyperphosphorylation and overactivation, increased resistance to multiple inhibitors (most of the tested PI3K inhibitors, Bruton tyrosine kinase inhibitor ibrutinib, and BCL2 inhibitor venetoclax), increased glycolytic rates with resistance to 2-deoxy-glucose, and significantly decreased dependence on prosurvival BCR signaling. Our results suggest that the frequent aberrations of the PI3K pathway may rewire associated signaling with lower dependence on BCR signaling, better metabolic and hypoxic adaptation, and targeted therapy resistance in MCL.

Transplantation, bridging, and support technologies in pulmonary hypertension.

Despite the progress made in medical therapies for treating pulmonary hypertension (PH), a subset of patients remain susceptible to developing a maladaptive right ventricular phenotype. The effective management of end-stage PH presents substantial challenges, necessitating a multidisciplinary approach and early identification of patients prone to acute decompensation. Identifying potential transplant candidates and assessing the feasibility of such a procedure are pivotal tasks that should be undertaken early in the treatment algorithm. Inclusion on the transplant list is contingent upon a comprehensive risk assessment, also considering the specific type of PH and various factors affecting waiting times, all of which should inform the decision-making process. While bilateral lung transplantation is the preferred option, it demands expert intra- and post-operative management to mitigate the heightened risks of pulmonary oedema and primary graft dysfunction in PH patients.Despite the availability of risk assessment tools, the occurrence of acute PH decompensation episodes can be unpredictable, potentially leading to refractory right ventricular failure even with optimal medical intervention, necessitating the use of rescue therapies. Advancements in right ventricular assist techniques and adjustments to graft allocation protocols for the most critically ill patients have significantly enhanced the survival in intensive care, affording the opportunity to endure while awaiting an urgent transplant. Given the breadth of therapeutic options available, specialised centres capable of delivering comprehensive care have become indispensable for optimising patient outcomes. These centres are instrumental in providing holistic support and management tailored to the complex needs of PH patients, ultimately enhancing their chances of a successful transplant and improved long-term prognosis.

Admission screening testing of patients and staff N95 respirators are cost-effective in reducing COVID-19 hospital-acquired infections.

BACKGROUND: Coronavirus disease 2019 (COVID-19) outbreaks in acute care settings can have severe consequences for patients due to their underlying vulnerabilities, and can be costly due to additional patient bed-days and the need to replace isolating staff. This study assessed the cost-effectiveness of clinical staff N95 respirators and admission screening testing of patients to reduce COVID-19 hospital-acquired infections. METHODS: An agent-based model was calibrated to data on 178 outbreaks in acute care settings in Victoria, Australia between October 2021 and July 2023. Outbreaks were simulated under different combinations of staff masking (surgical, N95) and patient admission screening testing [none, rapid antigen test (RAT), polymerase chain reaction]. For each scenario, average diagnoses, COVID-19 deaths, quality-adjusted life years from discharged patients, and costs (masks, testing, patient COVID-19 bed-days, staff replacement costs while isolating) from acute COVID-19 were estimated over a 12-month period. FINDINGS: Compared with no admission screening testing and staff surgical masks, all scenarios were cost saving with health gains. Staff N95 respirators + RAT admission screening of patients was the cheapest scenario, saving A$78.4M [95% uncertainty interval (UI) 44.4M-135.3M] and preventing 1543 (95% UI 1070-2146) deaths state-wide per annum. Both interventions were individually beneficial: staff N95 respirators saved A$54.7M and 854 deaths state-wide per annum, while RAT admission screening of patients saved A$57.6M and 1176 deaths state-wide per annum. INTERPRETATION: In acute care settings, staff N95 respirators and admission screening testing of patients can reduce hospital-acquired COVID-19 and COVID-19 deaths, and are cost saving because of reduced patient bed-days and staff replacement needs.

TRPS1 expression in MPNST is correlated with PRC2 inactivation and loss of H3K27me3.

Initially described as a highly specific immunohistochemical marker for carcinomas of mammary origin, trichorhinophalangeal syndrome type 1 (TRPS1) has subsequently been detected in a variety of other non-mammary tumors. In this study, we examined the immunohistochemical expression of TRPS1 in 114 peripheral nerve sheath tumors, including 43 malignant peripheral nerve sheath tumors (MPNSTs), 58 schwannomas, including 9 cellular neurofibromas, and 13 neurofibromas, including 1 atypical neurofibroma. Notably, TRPS1 was expressed in 49% of MPNSTs and was absent in all schwannomas and neurofibromas. All MPNSTs showed TRPS1 labeling in >50% of nuclei, with 95% of cases demonstrating diffuse labeling. Most cases (67%) showed weak TRPS1 immunoreactivity, while a smaller subset showed moderate (24%) or strong (9%) intensity staining. Analysis of publicly available gene expression datasets revealed higher levels of TRPS1 mRNA in MPNSTs with PRC2 inactivation. In keeping with this finding, TRPS1 expression was more commonly observed in MPNSTs with loss of H3K27me3, suggesting a potential relationship between TRPS1 and the PRC2 complex. This study further broadens the spectrum of TRPS1-expressing tumors to include MPNST.

Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022.

BACKGROUND: Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. CONCLUSIONS: We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.

Dehydrated Amnion Chorion Membrane versus standard of care for diabetic foot ulcers: a randomised controlled trial.

OBJECTIVE: Diabetic foot ulcers (DFUs) continue to challenge wound care practitioners. This prospective, multicentre, randomised controlled trial (RCT) evaluated the effectiveness of a dehydrated Amnion Chorion Membrane (dACM) (Organogenesis Inc., US) versus standard of care (SoC) alone in complex DFUs in a challenging patient population. METHOD: Subjects with a DFU extending into dermis, subcutaneous tissue, tendon, capsule, bone or joint were enrolled in a 12-week trial. They were allocated equally to two treatment groups: dACM (plus SoC); or SoC alone. The primary endpoint was frequency of wound closure determined by a Cox analysis that adjusted for duration and wound area. Kaplan-Meier analysis was used to determine median time to complete wound closure (CWC). RESULTS: The cohort comprised 218 patients, and these were split equally between the two treatment groups with 109 patients in each. A Cox analysis showed that the estimated frequency of wound closure for the dACM plus SoC group was statistically superior to the SoC alone group at week 4 (12% versus 8%), week 6 (22% versus 11%), week 8 (31% versus 21%), week 10 (42% versus 27%) and week 12 (50% versus 35%), respectively (p=0.04). The computed hazard ratio (1.48 (confidence interval: 0.95, 2.29) showed a 48% greater probability of wound closure in favour of the dACM group. Median time to wound closure for dACM-treated ulcers was 84 days compared to 'not achieved' in the SoC-treated group (i.e., ≥50% of SoC-treated DFUs failed to heal by week 12; p=0.04). CONCLUSION: In an adequately powered DFU RCT, dACM increased the frequency, decreased the median time, and improved the probability of CWC when compared with SoC alone. dACM demonstrated beneficial effects in DFUs in a complex patient population. DECLARATION OF INTEREST: This study was funded by Organogenesis Inc., US. JC serves as a consultant and speaker for Organogenesis. RDD serves as a speaker for Organogenesis. OMA and MLS serve as consultants for Organogenesis. The authors have no other conflicts of interest to declare.

The effect of different sweeteners on the oral microbiome: a randomized clinical exploratory pilot study.

Introduction: The aim of the study was to evaluate the modulating effects of five commonly used sweetener (glucose, inulin, isomaltulose, tagatose, trehalose) containing mouth rinses on the oral microbiome. Methods: A single-centre, double-blind, parallel randomized clinical trial was performed with healthy, 18-55-year-old volunteers (N = 65), who rinsed thrice-daily for two weeks with a 10% solution of one of the allocated sweeteners. Microbiota composition of supragingival dental plaque and the tongue dorsum coating was analysed by 16S RNA gene amplicon sequencing of the V4 hypervariable region (Illumina MiSeq). As secondary outcomes, dental plaque red fluorescence and salivary pH were measured. Results: Dental plaque microbiota changed significantly for two groups: inulin (F = 2.0239, p = 0.0006 PERMANOVA, Aitchison distance) and isomaltulose (F = 0.67, p = 0.0305). For the tongue microbiota, significant changes were observed for isomaltulose (F = 0.8382, p = 0.0452) and trehalose (F = 1.0119, p = 0.0098). In plaque, 13 species changed significantly for the inulin group, while for tongue coating, three species changed for the trehalose group (ALDEx2, p < 0.1). No significant changes were observed for the secondary outcomes. Conclusion: The effects on the oral microbiota were sweetener dependant with the most pronounced effect on plaque microbiota. Inulin exhibited the strongest microbial modulating potential of the sweeteners tested. Further full-scale clinical studies are required.

Targeting IL-11R/EZH2 signaling axis as a therapeutic strategy for osteosarcoma lung metastases.

Lung metastases are the primary cause of death for osteosarcoma (OS) patients. We recently validated interleukin-11 receptor α (IL-11Rα) as a molecular target for the inhibition of OS lung metastases. Since there is no clinically approved antibody against this receptor, we sought to identify downstream targets that mediate the effects of IL-11Rα signaling. We used shRNA to deplete IL-11Rα from OS cells; as a complementary approach, we added IL-11 exogenously to OS cells. The resulting changes in gene expression identified EZH2 as a downstream candidate. This was confirmed by knockdown of IL-11Rα in OS cells, which led to increased expression of genes repressed by histone methyltransferase EZH2, including members of the WNT pathway, a known target pathway of EZH2. Exogenous IL-11 increased the global levels of histone H3 lysine 27 trimethylation, evidence of EZH2 activation. Treatment with the EZH2 inhibitor GSK126 significantly reduced in vitro proliferation and increased cell-cycle arrest and apoptosis, which were partially mediated through the WNT pathway. In vivo, treatment of an orthotopic nude mouse model of OS with GSK126 inhibited lung metastatic growth and prolonged survival. In addition, significantly shorter recurrence-free survival was seen in OS patients with high levels of EZH2 in their primary tumors (P < .05). This suggests that IL-11Rα promotes OS lung metastasis via activation of EZH2. Thus, blocking EZH2 activity may be an effective strategy for inhibiting OS lung metastasis and improving prognosis.

Loss of the DNA Repair Gene RNase H2 Identifies a Unique Subset of DDR-Deficient Leiomyosarcomas.

Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR-targeted treatments. Therefore, we designed a protein- and genomic-based RNase H2 screening assay to determine its prevalence and prognostic significance. Using a selective RNase H2 antibody on a pan-tumor microarray (TMA), RNase H2 loss was more common in LMS (11.5%, 9/78) than across all tumors (3.8%, 32/843). In a separate LMS cohort, RNase H2 deficiency was confirmed in uterine LMS (U-LMS, 21%, 23/108) and soft-tissue LMS (ST-LMS; 30%, 39/102). In the TCGA database, RNASEH2B homozygous deletions (HomDels) were found in 6% (5/80) of LMS cases, with a higher proportion in U-LMS (15%; 4/27) compared with ST-LMS (2%; 1/53). Using the SNiPDx targeted-NGS sequencing assay to detect biallelic loss of function in select DDR-related genes, we found RNASEH2B HomDels in 54% (19/35) of U-LMS cases with RNase H2 loss by IHC, and 7% (3/43) HomDels in RNase H2 intact cases. No RNASEH2B HomDels were detected in ST-LMS. In U-LMS patient cohort (n = 109), no significant overall survival difference was seen in patients with RNase H2 loss versus intact, or RNASEH2B HomDel (n = 12) versus Non-HomDel (n = 37). The overall diagnostic accuracy, sensitivity, and specificity of RNase H2 IHC for detecting RNA-SEH2B HomDels in U-LMS was 76%, 93%, and 71%, respectively, and it is being developed for future predictive biomarker driven clinical trials targeting DDR in U-LMS.

Screening for symptoms of childhood traumatic stress in the primary care pediatric clinic.

BACKGROUND: Childhood traumatic experiences may result in post-traumatic stress disorder. Although pediatricians are encouraged to address these traumas in clinical encounters, measures of childhood traumatic stress have not been adopted by primary care clinicians. In this study, we describe the feasibility and potential utility of the UCLA Brief Screen, a validated screener for childhood traumatic stress symptoms, in pediatric primary care clinics. METHODS: Children 6-17 years of age presenting for routine well-child care in community-based pediatric clinics were eligible for traumatic stress screening. We described the feasibility and acceptability of screening based on screener adoption by eligible pediatric clinicians. We assessed the potential utility of screening based on prevalence and distribution of potentially traumatic events and traumatic stress symptoms in this general pediatric population. Finally, we compared results of the UCLA Brief Screen with those of the Patient Health Questionnaire-A to evaluate associations between symptoms of traumatic stress, depression, and suicidality among adolescents in this community setting. RESULTS: 14/18 (77.8%) pediatric clinicians in two clinics offered an adapted UCLA Brief Screen during 2359/4959 (47.6%) eligible well-child checks over 14 months. 1472/2359 (62.4%) of offered screeners were completed, returned, and scored. One-third (32.5%) of completed screeners captured a potentially traumatic event experience described by either children or caregivers. Moderate to severe traumatic stress symptoms were identified in 10.7% and 5.2% of patients, respectively. Concurrent depression screening revealed that 68.3% of adolescents with depressive symptoms reported a potentially traumatic event (PTE) and 80.5% had concurrent traumatic stress symptoms. Adolescents reporting a PTE were 3.5 times more likely to report thoughts of suicide or self-harm than those without this history. CONCLUSIONS: Results from this pilot study suggest that traumatic stress screening in the pediatric primary care setting may be feasible and may identify and classify mental health symptoms missed with current screening practices for depression. The prevalence of PTEs and traumatic stress symptoms associated with PTEs support the potential utility of a standardized screening in early identification of and response to children with clinically important symptoms of childhood traumatic stress. Future research should evaluate meaningful clinical outcomes associated with traumatic stress screening.

Insecticide susceptibility status of Anopheles gambiae mosquitoes and the effect of pre-exposure to a piperonyl butoxide (PBO) synergist on resistance to deltamethrin in northern Namibia.

BACKGROUND: Pyrethroid-based indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINs) have been employed as key vector control measures against malaria in Namibia. However, pyrethroid resistance in Anopheles mosquitoes may compromise the efficacy of these interventions. To address this challenge, the World Health Organization (WHO) recommends the use of piperonyl butoxide (PBO) LLINs in areas where pyrethroid resistance is confirmed to be mediated by mixed function oxidase (MFO). METHODS: This study assessed the susceptibility of Anopheles gambiae sensu lato (s.l.) mosquitoes to WHO tube bioassays with 4% DDT and 0.05% deltamethrin insecticides. Additionally, the study explored the effect of piperonyl butoxide (PBO) synergist by sequentially exposing mosquitoes to deltamethrin (0.05%) alone, PBO (4%) + deltamethrin (0.05%), and PBO alone. The Anopheles mosquitoes were further identified morphologically and molecularly. RESULTS: The findings revealed that An. gambiae sensu stricto (s.s.) (62%) was more prevalent than Anopheles arabiensis (38%). The WHO tube bioassays confirmed resistance to deltamethrin 0.05% in the Oshikoto, Kunene, and Kavango West regions, with mortality rates of 79, 86, and 67%, respectively. In contrast, An. arabiensis displayed resistance to deltamethrin 0.05% in Oshikoto (82% mortality) and reduced susceptibility in Kavango West (96% mortality). Notably, there was reduced susceptibility to DDT 4% in both An. gambiae s.s. and An. arabiensis from the Kavango West region. Subsequently, a subsample from PBO synergist assays in 2020 demonstrated a high proportion of An. arabiensis in Oshana (84.4%) and Oshikoto (73.6%), and 0.42% of Anopheles quadriannulatus in Oshana. Non-amplifiers were also present (15.2% in Oshana; 26.4% in Oshikoto). Deltamethrin resistance with less than 95% mortality, was consistently observed in An. gambiae s.l. populations across all sites in both 2020 and 2021. Following pre-exposure to the PBO synergist, susceptibility to deltamethrin was fully restored with 100.0% mortality at all sites in 2020 and 2021. CONCLUSIONS: Pyrethroid resistance has been identified in An. gambiae s.s. and An. arabiensis in the Kavango West, Kunene, and Oshikoto regions, indicating potential challenges for pyrethroid-based IRS and LLINs. Consequently, the data highlights the promise of pyrethroid-PBO LLINs in addressing resistance issues in the region.

Degradation trumps mutations in cancer.

Redirecting targeted proteins for degradation can overcome acquired drug resistance.

Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) Immunohistochemistry Can Be a Useful Ancillary Tool to Identify Perivascular Epithelioid Cell Tumor.

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors that express smooth muscle and melanocytic makers. Diagnosis of PEComas can be challenging due to focal or lost expression of traditional immunohistochemical markers, limited availability of molecular testing, and morphological overlap with much more common smooth muscle tumors. This study evaluates the use of glycoprotein nonmetastatic melanoma protein B (GPNMB) immunohistochemical staining as a surrogate marker for TSC1/2/MTOR alteration or TFE3 rearrangement to differentiate PEComas from other mesenchymal tumors. Cathepsin K was also assessed for comparison. A total of 399 tumors, including PEComas, alveolar soft part sarcomas, and other histologic PEComa mimics, were analyzed using GPNMB and cathepsin K immunohistochemistry. GPNMB expression was seen in all PEComas and alveolar soft part sarcomas with the majority showing diffuse and moderate-to-strong labeling, whereas other sarcomas were negative or showed focal labeling. When a cutoff of diffuse and at least moderate staining was used, GPNMB demonstrated 95% sensitivity and 97% specificity in distinguishing PEComas from leiomyosarcoma, well-differentiated/dedifferentiated liposarcomas, and undifferentiated pleomorphic sarcomas. Cathepsin K with a cutoff of any labeling had lower sensitivity (78%) and similar specificity (94%) to GPNMB. This study highlights GPNMB as a highly sensitive marker for PEComas and suggests its potential use as an ancillary tool within a panel of markers for accurate classification of these tumors.

Safety and efficacy of ibrutinib in combination with rituximab and lenalidomide in previously untreated follicular and marginal zone lymphoma: An open label, phase 2 study.

BACKGROUND: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent non-Hodgkin lymphomas (iNHL). Median survival for iNHL is approximately 20 years. Because standard treatments are not curative, patients often receive multiple lines of therapy with associated toxicity-rationally designed, combination therapies with curative potential are needed. The immunomodulatory drug lenalidomide was evaluated in combination with rituximab for the frontline treatment of FL in the phase 3 RELEVANCE study. Ibrutinib, an oral Bruton tyrosine kinase inhibitor, is active in NHL and was evaluated in combination with lenalidomide, rituximab, and ibrutinib (IRR) in a phase 1 study. METHODS: The authors conducted an open-label, phase 2 clinical trial of IRR for previously untreated FL and MZL. The primary end point was progression-free survival (PFS) at 24 months. RESULTS: This study included 48 participants with previously untreated FL grade 1-3a (N = 38), or MZL (N = 10). Participants received 12, 28-day cycles of lenalidomide (15 mg, days 1-21 cycle 1; 20 mg, cycles 2-12), rituximab (375 mg/m2 weekly in cycle 1; day 1 cycles 2-12), and ibrutinib 560 mg daily. With a median follow-up of 65.3 months, the estimated PFS at 24 months was 78.8% (95% confidence interval [CI], 68.0%-91.4%) and 60-month PFS was 59.7% (95% CI, 46.6%-76.4%). One death occurred unrelated to disease progression. Grade 3-4 adverse events were observed in 64.6%, including 50% with grade 3-4 rash. CONCLUSIONS: IRR is highly active as frontline therapy for FL and MZL. Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3-4 toxicity, particularly rash. The study was registered with ClinicalTrials.gov (NCT02532257).

Metal and metalloid content, bioavailability and sorption processes in glitter and raw glitter materials and associations with human and ecological risk concerns.

BACKGROUND: Microplastics comprise a significant group of emerging environmental contaminants with the capacity to adsorb several contaminants. These, in turn, undergo bioaccumulation and biomagnification processes throughout aquatic trophic chains. METHODS: Glitter, a microplastic powder composed of a combination of polymers, and raw glitter materials were investigated herein concerning metal and metalloid content, bioavailability, and sorption processes by inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: Metal and metalloid concentrations were higher in glitter than in raw glitter materials, but all were below the limits established by the Brazilian National Health Surveillance Agency. Elements present in glitter originate mainly from pigments and, thus, depend on glitter color. The bioavailability of the determined elements concerning human skin was assessed. Low desorbed concentrations in solution indicate that glitter does not represent a health risk through dermal contact concerning metal and metalloid contamination. However, several elements were shown to undergo significant desorption and adsorption processes. CONCLUSION: The findings reported herein indicate seemingly low human health risks from dermal glitter contact but reinforce glitter risks as aquatic environment metal and metalloid transport vectors.

Field-Based Planetary Protection Operations for Melt Probes: Validation of Clean Access into the Blood Falls, Antarctica, Englacial Ecosystem.

Subglacial environments on Earth offer important analogs to Ocean World targets in our solar system. These unique microbial ecosystems remain understudied due to the challenges of access through thick glacial ice (tens to hundreds of meters). Additionally, sub-ice collections must be conducted in a clean manner to ensure sample integrity for downstream microbiological and geochemical analyses. We describe the field-based cleaning of a melt probe that was used to collect brine samples from within a glacier conduit at Blood Falls, Antarctica, for geomicrobiological studies. We used a thermoelectric melting probe called the IceMole that was designed to be minimally invasive in that the logistical requirements in support of drilling operations were small and the probe could be cleaned, even in a remote field setting, so as to minimize potential contamination. In our study, the exterior bioburden on the IceMole was reduced to levels measured in most clean rooms, and below that of the ice surrounding our sampling target. Potential microbial contaminants were identified during the cleaning process; however, very few were detected in the final englacial sample collected with the IceMole and were present in extremely low abundances (∼0.063% of 16S rRNA gene amplicon sequences). This cleaning protocol can help minimize contamination when working in remote field locations, support microbiological sampling of terrestrial subglacial environments using melting probes, and help inform planetary protection challenges for Ocean World analog mission concepts.

Limb Amputations in Cancer: Modern Perspectives, Outcomes, and Alternatives.

PURPOSE OF REVIEW: This review summarizes current findings regarding limb amputation within the context of cancer, especially in osteosarcomas and other bony malignancies. We seek to answer the question of how amputation is utilized in the contemporary management of cancer as well as explore current advances in limb-sparing techniques. RECENT FINDINGS: The latest research on amputation has been sparse given its extensive history and application. However, new research has shown that rotationplasty, osseointegration, targeted muscle reinnervation (TMR), and regenerative peripheral nerve interfaces (RPNI) can provide patients with better functional outcomes than traditional amputation. While limb-sparing surgeries are the mainstay for managing musculoskeletal malignancies, limb amputation is useful as a palliative technique or as a primary treatment modality for more complex cancers. Currently, rotationplasty and osseointegration have been valuable limb-sparing techniques with osseointegration continuing to develop in recent years. TMR and RPNI have also been of interest in the modern management of patients requiring full or partial amputations, allowing for better control over myoelectric prostheses.

Generation of the iPSC line FINi002-A from a male Parkinson's disease patient carrying compound heterozygous mutations in the PRKN gene.

The most common cause of autosomal recessive familial Parkinson's disease (PD) are mutations in the PRKN/PARK2 gene encoding an E3 ubiquitin protein-ligase PARKIN. We report the generation of an iPSC cell line from the fibroblasts of a male PD patient carrying a common missense variant in exon 7 (p.Arg275Trp), and a 133 kb deletion encompassing exon 8, using transiently-present Sendai virus. The established line displays typical human primed iPSC morphology and expression of pluripotency-associated markers, normal karyotype without SNP array-detectable copy number variations and can give rise to derivatives of all three embryonic germ layers. We envisage the usefulness of this iPSC line, carrying a common and well-studied missense mutation in the RING1 domain of the PARKIN protein, for the elucidation of PARKIN-dependent mechanisms of PD using in vitro and in vivo models.