Post-market surveillance of six COVID-19 point-of-care tests using pre-Omicron and Omicron SARS-CoV-2 variants.

Post-market surveillance of test performance is a critical function of public health agencies and clinical researchers that ensures tests maintaining diagnostic characteristics following their regulatory approval. Changes in product quality, manufacturing processes over time, or the evolution of new variants may impact product performance. During the COVID-19 pandemic, a plethora of point-of-care tests (POCTs) was released onto the Canadian market. This study evaluated the performance characteristics of several of the most widely distributed POCTs in Canada, including four rapid antigen tests (Abbott Panbio, BTNX Rapid Response, SD Biosensor, and Quidel QuickVue) and two molecular tests (Abbott ID NOW and Lucira Check IT). All tests were challenged with 149 SARS-CoV-2 clinical positives, including multiple variants up to and including Omicron XBB.1.5, as well as 29 clinical negatives. Results were stratified based on whether the isolate was Omicron or pre-Omicron as well as by reverse transcriptase quantitative PCR Ct value. The test performance of each POCT was consistent with the manufacturers' claims and showed no significant decline in clinical performance against any of the variants tested. These findings provide continued confidence in the results of these POCTs as they continue to be used to support decentralized COVID-19 testing. This work demonstrates the essential role of post-market surveillance in ensuring reliability in diagnostic tools.IMPORTANCEPost-market surveillance of diagnostic test performance is critical to ensure their reliability after regulatory approval. This is especially critical in the context of the COVID-19 pandemic as the use of point-of-care tests (POCTs) became widespread. Our study focused on four rapid antigen tests (Abbott Panbio, BTNX Rapid Response, SD Biosensor, and Quidel QuickVue) and two molecular tests (Abbott ID NOW and Lucira Check IT) that were widely distributed across Canada, assessing their performance using many SARS-CoV-2 variants, including up to Omicron subvariant XBB.1.5. Overall, we found no significant difference in performance against any variant, reinforcing confidence in their use. As concerns in test efficacy have been raised by news outlets, particularly regarding the BTNX Rapid Response, this work is even more timely and crucial. Our research offers insights into the performance of widely used COVID-19 POCTs but also highlights the necessity for post-market surveillance.

Patent foramen ovale closure versus drug therapy in patients over 60 years and a follow-up of 5 years.

BACKGROUND: The advantages of patent foramen ovale (PFO) closure as protection from a recurrence of stroke remains controversial compared to drug therapy, especially in patients over 60 years. HYPOTHESIS: The aim of the study is to compare recurrence of stroke in patients over 60 years old with PFO closure versus drug therapy alone. METHODS: We included 342 patients over 60 years who suffered a crytopgenic stroke, and were also accepted for a PFO closure. 199 patients refused a PFO closure and were treated with medical therapy alone, whereas 143 patients underwent a PFO closure procedure. RESULTS: The mean follow up time was 5.5 ± 1.5 years. All patients in Group B showed persistent shunt in the follow-up period (n = 199, 100%). In Group A, seven patients were diagnosed with residual shunt during echocardiography examination (5%). A new onset of atrial fibrillation occurred in seven patients in Group A (5%) and six patients in Group B (3%), p = .117. Recurrent stroke occurred in 3 patients in Group A (2%) and 11 patients in Group B (6%), p = .021. One patient died of unknown reason (1%) and two patients were lost due to neurological death (1%) in Group B, whereas no patients in Group A died during the follow-up period. CONCLUSION: Our results show that strict exclusion of patients over 60 years from PFO closure should be reconsidered. As life expectancies are increasing, patients should be considered for same treatment as younger patients, since the outcomes are improved compared to patients treated with medical therapy alone.

Seven-year prospective study on yearly incidence of Orbivirus infection of captive white-tailed deer and potential Culicoides vectors.

Bluetongue virus (BTV) and epizootic hemorrhagic disease virus (EHDV) are arthropod-borne viruses that are transmitted by biting midges in the genus Culicoides (Diptera: Ceratopogonidae) and can cause hemorrhagic disease in certain ruminants. The objectives of this study were to measure the incidence of BTV and EHDV infections in captive white-tailed deer herd as well as tissues and corresponding presence of Culicoides midges at a location near Clinton, LA. During a 7-yr study with yearly outbreaks of hemorrhagic disease in the deer herd, 15 species of Culicoides were captured using Centers for Disease Control (CDC) black light traps. Reverse transcriptase quantitative polymerase chain reaction (PCR) was performed to screen for BTV and EHDV in pools of midges and tissues of deer. From 2012 to 2018, 1,711 pools of midges representing 24,859 specimens were tested, and specimens from 5 of the 15 collected species (Culicoides debilipalpis, Culicoides stellifer, Culicoides venustus, Culicoides haematopotus, and Culicoides crepuscularis) were found to be PCR positive for BTV and EHDV. Most of the BTV-positive pools of biting midges were from specimens of C. debilipalpis and C. stellifer, and most of the EHDV-positive pools were from specimens of C. venustus and C. stellifer. During the 7-yr period, 112 white-tailed deer that died at the study location were PCR positive for BTV or EHDV: detected BTV serotypes were 10 and 12 and EHDV serotypes were 1, 2, and 6. There was a significant increase in BTV/EHDV antibody prevalence in white-tailed deer during the study; antibody-positive rates increased from 15% to 78% in the deer herd of approximately 100 animals.

Student and Teacher Culture and Composition and the Development of Gender Role Attitudes among Young Adolescents.

Research has shown that gender role attitudes develop during adolescence; however, the relevant predictors remain a matter of debate. In adolescence, the school environment gains in importance. Thus, the present study investigates how students' and especially teachers' culture and composition predict the development of gender role attitudes in young adolescents. The study addresses this question using a sample of 7360 Flemish students (44.8% girls), who were surveyed three times after entering secondary education between 2012 (Mage = 13.14, SD = 0.56) and 2014. Latent change models reveal that boys' initial gender role attitudes are associated with the students' gender role culture; however, boys with more traditional gender role attitudes do not develop in an even more traditional direction at the beginning of secondary education. In contexts with a more privileged student SES composition, boys develop less traditional attitudes, while a traditional gender role culture among teachers supports the development of more traditional gender role attitudes among boys. Girls with more traditional gender role attitudes find themselves within student contexts with a more traditional culture. However, the development does not vary with the students' gender role culture. Overall, boys seem more susceptible to students' cultural and compositional characteristics.

Mental health and educational attainment: How developmental stage matters.

Developmental science suggests that the consequences of mental health problems for life-course outcomes may depend on the timing of their onset. This study investigated the extent to which mental health predicted educational attainment at ages 17, 20, and 25 and whether gender moderated the links between mental health and educational attainment. It used data from Next Steps, a nationally representative panel survey of individuals born in 1989/1990 in England (N = 15,594, 48% female, 33% ethnic minority). The findings suggest that differences in mental health were more consequential for educational attainment during adolescence than in young adulthood. On average, girls attained higher levels of education than boys, but gender did not moderate the role that mental health played for educational attainment. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Cultural Identity and the Academic, Social, and Psychological Adjustment of Adolescents with Immigration Background.

As Western societies become more ethnically and culturally diverse, understanding the acculturation of immigrant youth is essential for fostering social cohesion. How the cultural identity formation of ethnic minority adolescents relates to their academic, social, and psychological adjustment is an important and as yet unresolved research question. This study examined to what extent identifying with the heritage and/or host culture is an individual resource or risk factor for the adjustment of immigrant youth in Germany. A random sample of 15-17-year-olds (N = 1992; Mage_w1 = 15.3 years, SD = 0.64; 44.5% girls; 44.7% students with immigrant background) was assessed twice: at the end of 9th and 10th grade. Academic performance and three dimensions of social/psychological adjustment (school attachment, self-esteem, and life satisfaction) were examined. Results showed that biculturalism was the modal identification pattern. Contrary to expectations, cultural identification did not differ systematically with perceived distance from the majority culture. Multivariate structural equation modeling revealed that both heritage and host identification can be developmental resources, but that their effects are dependent on the dimension of adjustment; biculturalism only proved to be a cumulative resource for school attachment. The domain specificity of the findings challenges the generalization claims of predominant acculturation theories.

Establishment and Thorough Characterization of Xenograft (PDX) Models Derived from Patients with Pancreatic Cancer for Molecular Analyses and Chemosensitivity Testing.

Patient-derived xenograft (PDX) tumor models are essential for identifying new biomarkers, signaling pathways and novel targets, to better define key factors of therapy response and resistance mechanisms. Therefore, this study aimed at establishing pancreas carcinoma (PC) PDX models with thorough molecular characterization, and the identification of signatures defining responsiveness toward drug treatment. In total, 45 PC-PDXs were generated from 120 patient tumor specimens and the identity of PDX and corresponding patient tumors was validated. The majority of engrafted PDX models represent ductal adenocarcinomas (PDAC). The PDX growth characteristics were assessed, with great variations in doubling times (4 to 32 days). The mutational analyses revealed an individual mutational profile of the PDXs, predominantly showing alterations in the genes encoding KRAS, TP53, FAT1, KMT2D, MUC4, RNF213, ATR, MUC16, GNAS, RANBP2 and CDKN2A. Sensitivity of PDX toward standard of care (SoC) drugs gemcitabine, 5-fluorouracil, oxaliplatin and abraxane, and combinations thereof, revealed PDX models with sensitivity and resistance toward these treatments. We performed correlation analyses of drug sensitivity of these PDX models and their molecular profile to identify signatures for response and resistance. This study strongly supports the importance and value of PDX models for improvement in therapies of PC.

Changing patterns of otitis media in the Waikato region during the COVID-19 pandemic.

Introduction Acute otitis media (AOM) is a common condition of children encountered in general practice. A proportion of children develop otitis media with effusion (OME), which may require tympanostomy and ventilation tube insertion. Aim The aim of the study was to compare the incidence of AOM in Maori and New Zealand (NZ) European children in general practice and the referral practices to secondary care for tympanostomy and ventilation tube insertion. Methods The study was conducted in two parts: (1) an analysis of the incidence of AOM and OME in a rural Waikato general practice (Otorohanga) with a high Maori population over a 2-year period; and (2) an analysis of all referrals to the otorhinolaryngology (ORL) department at Waikato District Health Board and tympanostomy and ventilation tube insertion by this service over the same period. Results The incidence of AOM was similar in Maori compared with NZ European children. The incidence declined significantly between 2019 and 2020 and 50% of children with AOM were treated with antibiotics. Referral rates to the ORL department were greater for Maori compared with NZ European children as were tympanostomy and ventilation tube insertion rates. Discussion Although AOM is common, OME was rarely diagnosed. The clinical guidelines regarding antibiotic use for common conditions are not being readily adopted and further research is needed into this matter. The COVID-19 pandemic had a substantial effect on demand both in general practice and in the hospital sector. This may have been due to a reduction in the incidence of AOM or due to system changes caused by the pandemic.

Assessment of rapid wastewater surveillance for determination of communicable disease spread in municipalities.

Wastewater surveillance (WS) helps to improve the understanding of the spread of communicable diseases in communities. WS can assist public health decision-makers in the design and implementation of timely mitigation measures. There is an increased need to use reliable, cost-effective, simple, and rapid WS systems, given traditional analytical (or 'gold-standard') programs are instrument/time-intensive, and dependent on highly skilled personnel. This study investigated the application of the portable GeneXpert platform for WS of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus (IAV), influenza B virus (IBV), and respiratory syncytial virus (RSV). The GeneXpert system with the Xpert Xpress-SARS-CoV-2/Flu/RSV test kit uses reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to analyze wastewater samples. From September 2022 through January 2023, wastewater samples were collected from the influents of municipal wastewater treatment plants (MWTPs) of Saskatoon, Prince Albert, and North Battleford in the province of Saskatchewan, Canada. Both raw and concentrated wastewater samples were subjected to the GeneXpert analysis. Results showed that the Saskatoon wastewater viral loads were significantly correlated to Saskatchewan's influenza and COVID-19 clinical cases, with a lead time of 10 days for IAV and a lag time of 4 days for SARS-CoV-2. Additionally, the GeneXpert analysis of the three cities' wastewater samples showed that the raw WS could capture the dynamics of SARS-CoV-2 and IAV due to their correlation with concentrated WS. Interestingly, IBV loads were not detected in any wastewater samples, while the Saskatoon and Prince Albert wastewater samples collected following the 2023 holiday season (end of December and beginning of January) were positive for RSV. This study indicates that the GeneXpert has excellent potential for use in the development of an early warning system for transmissible disease in municipalities and limited-resource communities while simultaneously providing stakeholders with an efficient WS methodology.

Echocardiographic determination of right ventricular volumes and ejection fraction: Validation of a truncated cone and rhomboid pyramid formula.

BACKGROUND: Echocardiographic assessment of right ventricular (RV) measurements may be challenging. The aim of this study was to develop a formula for calculation of RV volumes and function based on measurements of linear dimensions by 2-dimensional (2D) transthoracic echocardiography (TTE) in comparison to cardiovascular magnetic resonance (CMR). METHODS: 129 consecutive patients with standard TTE and RV analysis by CMR were included. A formula based on the geometric assumptions of a truncated cone minus a truncated rhomboid pyramid was developed for calculations of RV end-diastolic volume (EDV) and RV end-systolic volume (ESV) by using the basal diameter of the RV (Dd and Ds) and the baso-apical length (Ld and Ls) in apical 4-chamber TTE views: RV EDV = 1.21 * Dd2 * Ld, and RV ESV = 1.21 * Ds2 * Ls. RESULTS: Calculations of RV EDV (ΔRV EDV = 10.2±26.4 ml to CMR, r = 0.889), RV ESV (ΔRV ESV = 4.5±18.4 ml to CMR, r = 0.921) and RV EF (ΔRV EF = 0.5±4.0% to CMR, r = 0.905) with the cone-pyramid formula (CPF) highly agreed with CMR. Impaired RV function on CMR (n = 52) was identified with a trend to higher accuracy by CPF than by conventional echocardiographic parameters (tricuspid annular plane systolic excursion (TAPSE) and fractional area change (FAC)). CONCLUSION: Calculations of RV volumes and RV function by 2D TTE with the newly developed CPF were in high concordance to measurements by CMR. Accuracy for detection of patients with reduced RV function were higher by the proposed 2D TTE CPF method than by conventional echocardiographic parameters of TAPSE and RV FAC.

Conventional vs. Sutureless Aortic Valve Bioprosthesis: Is Faster Better?

Purpose: The benefits of sutureless compared to conventional aortic valve prosthesis replacement remain controversial. Supposed advantages of sutureless aortic valve replacement include shortened cross-clamp and implantation time, as well as improved overall safety and good post-operative performance. We aimed to compare the early outcomes and performance of sutureless aortic valve replacement (su-AVR) with the sutureless Perceval (Corcym, Milan, Italy) vs. the conventional AVR with a conventional counterpart, in this case, the Labcor Dokimos Plus (LDP) aortic bioprosthesis. Methods: We compared two types of aortic valve prostheses, the sutureless (Corcym, Milan, Italy) and the conventional valve Labcor Dokimos Plus (LDP), implanted between August 2014 and May 2019 in our Department of Cardiac Surgery at RWTH Aachen University Hospital. Data were collected from 141 patients who received the Perceval (Corcym, Milan, Italy) and 138 who received the Labcor Dokimos Plus (LDP) aortic bioprosthesis. After matching the two groups considering STS mortality risk and pre-operative LDH levels, 201 patients were included in our final study cohort. Seventy-one patients (17 from the Perceval group and 54 from the Dokimos group) were excluded due to the lack of complete data, particularly standardized echocardiographic data (n = 71). Primary endpoints were 30-day mortality, length of hospital stay, and pacemaker implantation. Secondary endpoints were echocardiographic parameters, major adverse cardiovascular events, and prosthesis failure (grade II aortic regurgitation, paravalvular leak with reintervention). Results: Bypass and cross-clamp time proved to be shorter in the Perceval group, while hospital stays were longer. The faster implantation had no effect on the 30-day mortality primary endpoint. Transvalvular gradients were significantly higher in the Perceval group, in addition to a smaller effective orifice area. The LDH values were remarkably higher post-operatively in the Perceval group. Conclusions: Regarding the clinical outcomes, Perceval was equivalent and not superior to the Dokimus bioprosthesis. The suitability of a Perceval prosthesis implantation must be determined on a case-by-case basis and reserved for elderly patients with increased comorbidity.

Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1.

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.

Efferocytosis by bone marrow mesenchymal stromal cells disrupts osteoblastic differentiation via mitochondrial remodeling.

The efficient clearance of dead and dying cells, efferocytosis, is critical to maintain tissue homeostasis. In the bone marrow microenvironment (BMME), this role is primarily fulfilled by professional bone marrow macrophages, but recent work has shown that mesenchymal stromal cells (MSCs) act as a non-professional phagocyte within the BMME. However, little is known about the mechanism and impact of efferocytosis on MSCs and on their function. To investigate, we performed flow cytometric analysis of neutrophil uptake by ST2 cells, a murine bone marrow-derived stromal cell line, and in murine primary bone marrow-derived stromal cells. Transcriptional analysis showed that MSCs possess the necessary receptors and internal processing machinery to conduct efferocytosis, with Axl and Tyro3 serving as the main receptors, while MerTK was not expressed. Moreover, the expression of these receptors was modulated by efferocytic behavior, regardless of apoptotic target. MSCs derived from human bone marrow also demonstrated efferocytic behavior, showing that MSC efferocytosis is conserved. In all MSCs, efferocytosis impaired osteoblastic differentiation. Transcriptional analysis and functional assays identified downregulation in MSC mitochondrial function upon efferocytosis. Experimentally, efferocytosis induced mitochondrial fission in MSCs. Pharmacologic inhibition of mitochondrial fission in MSCs not only decreased efferocytic activity but also rescued osteoblastic differentiation, demonstrating that efferocytosis-mediated mitochondrial remodeling plays a critical role in regulating MSC differentiation. This work describes a novel function of MSCs as non-professional phagocytes within the BMME and demonstrates that efferocytosis by MSCs plays a key role in directing mitochondrial remodeling and MSC differentiation. Efferocytosis by MSCs may therefore be a novel mechanism of dysfunction and senescence. Since our data in human MSCs show that MSC efferocytosis is conserved, the consequences of MSC efferocytosis may impact the behavior of these cells in the human skeleton, including bone marrow remodeling and bone loss in the setting of aging, cancer and other diseases.

Mitochondrial Transfer to Host Cells from Ex Vivo Expanded Donor Hematopoietic Stem Cells.

Mitochondrial dysfunction is observed in various conditions, from metabolic syndromes to mitochondrial diseases. Moreover, mitochondrial DNA (mtDNA) transfer is an emerging mechanism that enables the restoration of mitochondrial function in damaged cells. Hence, developing a technology that facilitates the transfer of mtDNA can be a promising strategy for the treatment of these conditions. Here, we utilized an ex vivo culture of mouse hematopoietic stem cells (HSCs) and succeeded in expanding the HSCs efficiently. Upon transplantation, sufficient donor HSC engraftment was attained in-host. To assess the mitochondrial transfer via donor HSCs, we used mitochondrial-nuclear exchange (MNX) mice with nuclei from C57BL/6J and mitochondria from the C3H/HeN strain. Cells from MNX mice have C57BL/6J immunophenotype and C3H/HeN mtDNA, which is known to confer a higher stress resistance to mitochondria. Ex vivo expanded MNX HSCs were transplanted into irradiated C57BL/6J mice and the analyses were performed at six weeks post transplantation. We observed high engraftment of the donor cells in the bone marrow. We also found that HSCs from the MNX mice could transfer mtDNA to the host cells. This work highlights the utility of ex vivo expanded HSC to achieve the mitochondrial transfer from donor to host in the transplant setting.

In Vitro Biofouling Performance of Boron-Doped Diamond Microelectrodes for Serotonin Detection Using Fast-Scan Cyclic Voltammetry.

Neurotransmitter release is important to study in order to better understand neurological diseases and treatment approaches. Serotonin is a neurotransmitter known to play key roles in the etiology of neuropsychiatric disorders. Fast-scan cyclic voltammetry (FSCV) has enabled the detection of neurochemicals, including serotonin, on a sub-second timescale via the well-established carbon fiber microelectrode (CFME). However, poor chronic stability and biofouling, i.e., the adsorption of interferent proteins to the electrode surface upon implantation, pose challenges in the natural physiological environment. We have recently developed a uniquely designed, freestanding, all-diamond boron-doped diamond microelectrode (BDDME) for electrochemical measurements. Key potential advantages of the device include customizable electrode site layouts, a wider working potential window, improved stability, and resistance to biofouling. Here, we present a first report on the electrochemical behavior of the BDDME in comparison with CFME by investigating in vitro serotonin (5-HT) responses with varying FSCV waveform parameters and biofouling conditions. While the CFME delivered lower limits of detection, we also found that BDDMEs showed more sustained 5-HT responses to increasing or changing FSCV waveform-switching potential and frequency, as well as to higher analyte concentrations. Biofouling-induced current reductions were significantly less pronounced at the BDDME when using a "Jackson" waveform compared to CFMEs. These findings are important steps towards the development and optimization of the BDDME as a chronically implanted biosensor for in vivo neurotransmitter detection.

Myelodysplastic syndromes disable human CD271+VCAM1+CD146+ niches supporting normal hematopoietic stem/progenitor cells.

Mesenchymal stem/stromal cells (MSCs) within the bone marrow microenvironment (BMME) support normal hematopoietic stem and progenitor cells (HSPCs). However, the heterogeneity of human MSCs has limited the understanding of their contribution to clonal dynamics and evolution to myelodysplastic syndromes (MDS). We combined three MSC cell surface markers, CD271, VCAM-1 (Vascular Cell Adhesion Molecule-1) and CD146, to isolate distinct subsets of human MSCs from bone marrow aspirates of healthy controls (Control BM). Based on transcriptional and functional analysis, CD271+CD106+CD146+ (NGFR+/VCAM1+/MCAM+/Lin-; NVML) cells display stem cell characteristics, are compatible with murine BM-derived Leptin receptor positive MSCs and provide superior support for normal HSPCs. MSC subsets from 17 patients with MDS demonstrated shared transcriptional changes in spite of mutational heterogeneity in the MDS clones, with loss of preferential support of normal HSPCs by MDS-derived NVML cells. Our data provide a new approach to dissect microenvironment-dependent mechanisms regulating clonal dynamics and progression of MDS.

Clinically relevant glioblastoma patient-derived xenograft models to guide drug development and identify molecular signatures.

Glioblastoma (GBM) heterogeneity, aggressiveness and infiltrative growth drastically limit success of current standard of care drugs and efficacy of various new therapeutic approaches. There is a need for new therapies and models reflecting the complex biology of these tumors to analyze the molecular mechanisms of tumor formation and resistance, as well as to identify new therapeutic targets. We established and screened a panel of 26 patient-derived subcutaneous (s.c.) xenograft (PDX) GBM models on immunodeficient mice, of which 15 were also established as orthotopic models. Sensitivity toward a drug panel, selected for their different modes of action, was determined. Best treatment responses were observed for standard of care temozolomide, irinotecan and bevacizumab. Matching orthotopic models frequently show reduced sensitivity, as the blood-brain barrier limits crossing of the drugs to the GBM. Molecular characterization of 23 PDX identified all of them as IDH-wt (R132) with frequent mutations in EGFR, TP53, FAT1, and within the PI3K/Akt/mTOR pathway. Their expression profiles resemble proposed molecular GBM subtypes mesenchymal, proneural and classical, with pronounced clustering for gene sets related to angiogenesis and MAPK signaling. Subsequent gene set enrichment analysis identified hallmark gene sets of hypoxia and mTORC1 signaling as enriched in temozolomide resistant PDX. In models sensitive for mTOR inhibitor everolimus, hypoxia-related gene sets reactive oxygen species pathway and angiogenesis were enriched. Our results highlight how our platform of s.c. GBM PDX can reflect the complex, heterogeneous biology of GBM. Combined with transcriptome analyses, it is a valuable tool in identification of molecular signatures correlating with monitored responses. Available matching orthotopic PDX models can be used to assess the impact of the tumor microenvironment and blood-brain barrier on efficacy. Our GBM PDX panel therefore represents a valuable platform for screening regarding molecular markers and pharmacologically active drugs, as well as optimizing delivery of active drugs to the tumor.

The roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies.

Prior research establishing that bone interacts in coordination with the bone marrow microenvironment (BMME) to regulate hematopoietic homeostasis was largely based on analyses of individual bone-associated cell populations. Recent advances in intravital imaging has suggested that the expansion of hematopoietic stem cells (HSCs) and acute myeloid leukemia cells is restricted to bone marrow microdomains during a distinct stage of bone remodeling. These findings indicate that dynamic bone remodeling likely imposes additional heterogeneity within the BMME to yield differential clonal responses. A holistic understanding of the role of bone remodeling in regulating the stem cell niche and how these interactions are altered in age-related hematological malignancies will be critical to the development of novel interventions. To advance this understanding, herein, we provide a synopsis of the cellular and molecular constituents that participate in bone turnover and their known connections to the hematopoietic compartment. Specifically, we elaborate on the coupling between bone remodeling and the BMME in homeostasis and age-related hematological malignancies and after treatment with bone-targeting approaches. We then discuss unresolved questions and ambiguities that remain in the field.