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Purpose of Review: Kidney stone disease is recognized to negatively impact quality of life. This pertains to acute episodes, surgical interventions and even during asymptomatic periods. Over time there has been increased attention towards assessing this subjective parameter, including as a determinant of treatment success. Our aim was to evaluate the current status and emerging trends in this field., Recent Findings: Patient groups most affected appear to be recurrent stone formers, cystine stone formers, women, younger populations, non-Caucasians and low-income populations. Several stone specific patient reported outcome measures are now available of which, WISQol has been implemented the most in clinical research studies. More invasive interventions such as percutaneous nephrolithotomy impede quality of life to greater extent than alternatives such as shockwave lithotripsy., Summary: There are certain patient groups who are more vulnerable to the negative impact of kidney stone disease on their quality of life. Urologists can improve patient care by recognizing these particular populations as well as by implemented patient reported outcome measures in their routine clinical practice and when performing research., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Digitalization of health care has opened up for new ways to involve and engage patients. With this, increased attention has been put on digital patient portals. There exists some research on patient portals for adolescent patients in general and for adults in mental health care. However, no studies on patient portals for adolescents in mental health care have been identified in a recent review. The aim was therefore to explore the views on using patient portals for adolescents in mental health care among persons involved in and/or being affected by the introduction of a patient portal. Methods: A qualitative study was conducted using individual semi-structured interviews with 14 persons who were healthcare providers in child and adolescent mental health care, young representatives from the user panel, or persons affiliated with an EHR-project introducing a patient portal. The main questions addressed their views on introducing patient portals for adolescents in mental health care and how patient portals and access to clinical notes can affect them and their treatment. Results: The findings were categorised into four main themes; “Does access to a patient portal help or harm adolescents?”, “Who decides access?”, “Mostly a political goal” and “Need for support and competency”. Informants mentioned situations in which both adolescents’ and parents’ access to a patient portal could help adolescents in mental health care, but also where it could potentially harm their treatment and threaten confidentiality. Most informants thought that healthcare providers should have the autonomy to determine which information should be shared with whom, but also requested guidelines to ensure equal practice and support in difficult situations. Some perceived patient portals as the result of a political decision, rather than healthcare providers´ wishes, while others described it as a necessary development towards democratization. Conclusion: The informants’ views varied from thinking that a patient portal could support adolescents in mental health care, to worrying that it could be detrimental to the treatment. Informants emphasized that the management should facilitate training and support for healthcare providers in using patient portals and telehealth. [ABSTRACT FROM AUTHOR]

Current literature yields unequivocal results regarding the effect of body composition on physical function in patients with chronic obstructive pulmonary disease and disproportionately includes a majority of males. The purpose of this study was to determine whether specific body composition measures are significantly associated with physical function and exercise capacity in patients with chronic obstructive pulmonary disease with equal representation of males and females. Independent variables included sex, total body mass, total body lean and fat mass, appendicular total mass, and appendicular lean and fat mass. Dependent variables included peak oxygen consumption, 6-minute walk distance and self-reported physical function. Patients (n = 170) with dual-energy X-ray absorptiometry data, 6-minute walk distance, and self-reported physical function were used for these analyses. A sub-set of 145 of these patients with peak oxygen consumption data were also analysed. Hierarchical multiple regression analysis was used to determine if sex and body composition measures correlated with physical function and exercise capacity and if they explained additional variance after controlling for disease severity. After controlling for disease severity, appendicular lean mass, total body fat mass, and sex explained an additional 16.5% of the variance in peak oxygen consumption (p < 0.001). Appendicular lean mass explained an additional 8.9% of the variance in 6-minute walk distance (p < 0.001) and an additional 2.5% of the variance in self-reported physical function (p = 0.057). Body composition measures may further predict exercise capacity, 6-minute walk distance, and self-reported physical function in patients with chronic obstructive pulmonary disease. [ABSTRACT FROM AUTHOR]

Background: Health care providers (HCPs) in the emergency department (ED) frequently must decide whether to conduct or forego confidential conversations with adolescent patients about sensitive topics, such as those related to mental health, substance use, and sexual and reproductive health. The objective of this multicenter qualitative analysis was to identify factors that influence the conduct of confidential conversations with adolescent patients in the ED. Methods: In this qualitative study, we conducted semistructured interviews of ED HCPs from five academic, pediatric EDs in distinct geographic regions. We purposively sampled HCPs across gender, professional title, and professional experience. We used the Theoretical Domains Framework (TDF) to develop an interview guide to assess individual and system‐level factors affecting HCP behavior regarding the conduct of confidential conversations with adolescents. Enrollment continued until we reached saturation. Interviews were recorded, transcribed, and coded by three investigators based on thematic analysis. We used the coded transcripts to collaboratively generate belief statements, which are first‐person statements that reflect shared perspectives. Results: We conducted 38 interviews (18 physicians, 11 registered nurses, five nurse practitioners, and four physician assistants). We generated 17 belief statements across nine TDF domains. Predominant influences on having confidential conversations included self‐efficacy in speaking with adolescents alone, wanting to address sexual health complaints, maintaining patient flow, experiencing parental resistance and limited space, and having inadequate resources to address patient concerns and personal preconceptions about patients. Perspectives divided between wanting to provide focused medical care related only to their chief complaint versus self‐identifying as a holistic medical HCP. Conclusions: The factors influencing the conduct of confidential conversations included multiple TDF domains, elucidating how numerous intersecting factors influence whether ED HCPs address sensitive adolescent health needs. These data suggest methods to enhance and facilitate confidential conversations when deemed appropriate in the care of adolescents in the ED. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV; human herpesvirus 4; HHV‐4) and Kaposi sarcoma‐associated herpesvirus (KSHV; human herpesvirus 8; HHV‐8) are human gammaherpesviruses that have oncogenic properties. EBV is a lymphocryptovirus, whereas HHV‐8/KSHV is a rhadinovirus. As lymphotropic viruses, EBV and KSHV are associated with several lymphoproliferative diseases or plasmacytic/plasmablastic neoplasms. Interestingly, these viruses can also infect epithelial cells causing carcinomas and, in the case of KSHV, endothelial cells, causing sarcoma. EBV is associated with Burkitt lymphoma, classic Hodgkin lymphoma, nasopharyngeal carcinoma, plasmablastic lymphoma, lymphomatoid granulomatosis, leiomyosarcoma, and subsets of diffuse large B‐cell lymphoma, post‐transplant lymphoproliferative disorder, and gastric carcinoma. KSHV is implicated in Kaposi sarcoma, primary effusion lymphoma, multicentric Castleman disease, and KSHV‐positive diffuse large B‐cell lymphoma. Pathogenesis by these two herpesviruses is intrinsically linked to viral proteins expressed during the lytic and latent lifecycles. This comprehensive review intends to provide an overview of the EBV and KSHV viral cycles, viral proteins that contribute to oncogenesis, and the current understanding of the pathogenesis and clinicopathology of their related neoplastic entities. [ABSTRACT FROM AUTHOR]

Cystinuria is a rare disorder resulting in development of recurrent kidney stones, adversely affecting patient quality of life. The goal of cystinuria management is to reduce stone formation by increasing cystine solubility in urine, which includes lowering the urinary cystine level below its solubility limit. Treatment usually involves alkalinization of the urine and often requires initiating pharmacotherapy with a cystine-binding thiol drug (CBTD) such as tiopronin; however, proper dose adjustment requires accurate measurement of urinary cystine. The goal of this study was to validate a novel high-performance liquid chromatography tandem mass spectrometry (HPLC–MS/MS) method for quantification of cystine in the urine of patients with cystinuria receiving a CBTD. Urine samples were collected over 24 h from 24 patients and separated into 2 aliquots. Chromatographic separation of samples was conducted and separation of cystine from the cysteine-tiopronin drug complex was complete in < 3 min. The method was validated for accuracy, precision, linearity, limit of detection (LOD), and limit of quantification (LOQ). Mean accuracy range was 97.7–102.3%; intermediate precision was high with relative percent difference values calculated at 1.2–9.3%; the calibration curve resulted in a linear response throughout the concentration range (R2 = 0.998); and the LOD and LOQ were 0.002 and 0.005 mg/mL, respectively. Mean (range) cystine concentrations measured were 111.10 (51.31–179.46) and 242.21 (61.14–741.80) g/L in Aliquots A and B, respectively. The HPLC–MS/MS method presented here indicates that urine cystine can be reliably quantified in patients receiving a CBTD. [ABSTRACT FROM AUTHOR]

RO7297089, an anti-B-cell maturation antigen (BCMA)/CD16A bispecific tetravalent antibody, is being developed as a multiple myeloma (MM) therapeutic. This study characterized nonclinical pharmacokinetics (PK), pharmacodynamics (PD), soluble BCMA (sBCMA), and soluble CD16 (sCD16) changes following administration of RO7297089 to support clinical trials. Unbound and total RO7297089 concentrations were measured in cynomolgus monkeys. RO7297089 exhibited a bi-phasic systemic concentration-time profile, similar to a typical human immunoglobulin 1 antibody. Target engagement by RO7297089 led to a robust increase (~100-fold) in total systemic sBCMA levels and relatively mild increase (~2-fold) in total sCD16 levels. To describe the relationship of nonclinical PK/PD data, we developed a target-mediated drug disposition (TMDD) model that includes the systemic target engagement of membrane BCMA (mBCMA), sBCMA, membrane CD16 (mCD16), and sCD16. We then used this model to simulate the PK/PD relationship of RO7297089 in MM patients by translating relevant PK parameters and target levels, based on the literature and newly generated data such as baseline sCD16A levels. Our model suggested that the impact of TMDD on RO7297089 exposure may be more significant in MM patients due to significantly higher expression levels of both mBCMA and sBCMA compared to healthy cynomolgus monkeys. Based on model simulations, we propose more frequent dosing of RO7297089 compared to regular monthly frequency in the clinic at the beginning of treatment to ensure sustained target engagement. This study demonstrates a translational research strategy for collecting relevant nonclinical data, establishing a TMDD model, and using simulations from this model to inform clinical dose regimens. [ABSTRACT FROM AUTHOR]

We investigated independent associations between telomere length and risk of fracture and arthroplasty in UK Biobank participants. Leukocyte telomere length (LTL) was measured in baseline samples using a validated polymerase chain reaction (PCR) method. We used, in men and women separately, Cox proportional hazards models to calculate the hazard ratio (HR) for incident fracture (any, osteoporotic) or arthroplasty (hip or knee) over 1,186,410 person‐years of follow‐up. Covariates included age, white cell count, ethnicity, smoking, alcohol, physical activity, and menopause (women). In further analyses we adjusted for either estimated bone mineral density (eBMD) from heel quantitative ultrasound, handgrip strength, gait speed, total fat mass (bioimpedance), or blood biomarkers, all measured at baseline (2006–2010). We studied 59,500 women and 51,895 men, mean ± standard deviation (SD) age 56.4 ± 8.0 and 57.0 ± 8.3 years, respectively. During follow‐up there were 5619 fractures; 5285 hip and 4261 knee arthroplasties. In confounder‐adjusted models, longer LTL was associated with reduced risk of incident knee arthroplasty in both men (HR/SD 0.93; 95% confidence interval [CI], 0.88–0.97) and women (0.92; 95% CI, 0.88–0.96), and hip arthroplasty in men (0.91; 95% CI, 0.87–0.95), but not women (0.98; 95% CI, 0.94–1.01). Longer LTL was weakly associated with reduced risk of any incident fracture in women (HR/SD 0.96; 95% CI, 0.93–1.00) with less evidence in men (0.98; 95% CI, 0.93–1.02). Associations with incident outcomes were not materially altered by adjustment for heel eBMD, grip strength, gait speed, fat mass, or blood biomarker measures. In this, the largest study to date, longer LTL was associated with lower risk of incident knee or hip arthroplasty, but only weakly associated with lower risk of fracture. The relative risks were low at a population level, but our findings suggest that common factors acting on the myeloid and musculoskeletal systems might influence later life musculoskeletal outcomes. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Objectives: Despite advances in antibody treatments and vaccines, COVID‐19 caused by SARS‐CoV‐2 infection remains a major health problem resulting in excessive morbidity and mortality and the emergence of new variants has reduced the effectiveness of current vaccines. Methods: Here, as a proof‐of‐concept, we engineered primary CD8 T cells to express SARS‐CoV‐2 Spike protein‐specific CARs, using the extracellular region of ACE2 and demonstrated their highly specific and potent cytotoxicity towards Spike‐expressing target cells. To improve on this concept as a potential therapeutic, we developed a bispecific T cell engager combining ACE2 with an anti‐CD3 scFv (ACE2‐Bite) to target infected cells and the virus. Results: As in CAR‐T cell approach, ACE2‐Bite endowed cytotoxic cells to selectively kill Spike‐expressing targets. Furthermore, ACE2‐Bite neutralized the pseudoviruses of SARS‐CoV, SARS‐CoV‐2 wild‐type, and variants including Delta and Omicron, as a decoy protein. Remarkably, ACE2‐Bite molecule showed a higher binding and neutralization affinity to Delta and Omicron variants compared to SARS‐CoV‐2 wild‐type Spike proteins. Conclusion: In conclusion, these results suggest the potential of this approach as a variant‐proof, therapeutic strategy for future SARS‐CoV‐2 variants, employing both humoral and cellular arms of the adaptive immune response. [ABSTRACT FROM AUTHOR]

CD47 is a marker of self and a signaling receptor for thrombospondin-1 that is also a component of extracellular vesicles (EVs) released by various cell types. Previous studies identified CD47-dependent functional effects of T cell EVs on target cells, mediated by delivery of their RNA contents, and enrichment of specific subsets of coding and noncoding RNAs in CD47+ EVs. Mass spectrometry was employed here to identify potential mechanisms by which CD47 regulates the trafficking of specific RNAs to EVs. Specific interactions of CD47 and its cytoplasmic adapter ubiquilin-1 with components of the exportin-1/Ran nuclear export complex were identified and confirmed by coimmunoprecipitation. Exportin-1 is known to regulate nuclear to cytoplasmic trafficking of 5'-7-methylguanosine (m7G)-modified microRNAs and mRNAs that interact with its cargo protein EIF4E. Interaction with CD47 was inhibited following alkylation of exportin-1 at Cys528 by its covalent inhibitor leptomycin B. Leptomycin B increased levels of m7G-modified RNAs, and their association with exportin-1 in EVs released from wild type but not CD47-deficient cells. In addition to perturbing nuclear to cytoplasmic transport, transcriptomic analyses of EVs released by wild type and CD47-deficient Jurkat T cells revealed a global CD47-dependent enrichment of m7G-modified microRNAs and mRNAs in EVs released by CD47-deficient cells. Correspondingly, decreasing CD47 expression in wild type cells or treatment with thrombospondin-1 enhanced levels of specific m7G-modified RNAs released in EVs, and re-expressing CD47 in CD47-deficient T cells decreased their levels. Therefore, CD47 signaling limits the trafficking of m7G-modified RNAs to EVs through physical interactions with the exportin-1/Ran transport complex. [ABSTRACT FROM AUTHOR]

Purpose: This secondary exploratory analysis examined rural-urban differences in response to a web-based physical activity self-management intervention for chronic obstructive pulmonary disease (COPD)., Methods: Participants with COPD (N = 239 US Veterans) were randomized to either a multicomponent web-based intervention (goal setting, iterative feedback of daily step counts, motivational and educational information, and an online community forum) or waitlist-control for 4 months with a 12-month follow-up. General linear modeling estimated the impact of rural/urban status (using Rural-Urban Commuting Area [RUCA] codes) on (1) 4- and 12-month daily step-count change compared to waitlist-control, and (2) intervention engagement (weekly logons and participant feedback)., Findings: Rural (n = 108) and urban (n = 131) participants' mean age was 66.7±8.8 years. Rural/urban status significantly moderated 4-month change in daily step counts between randomization groups (p = 0.041). Specifically, among urban participants, intervention participants improved by 1500 daily steps more than waitlist-control participants (p = 0.001). There was no difference among rural participants. In the intervention group, rural participants engaged less with the step-count graphs on the website than urban participants at 4 months (p = 0.019); this difference dissipated at 12 months. More frequent logons were associated with greater change in daily step counts (p = 0.004); this association was not moderated by rural/urban status., Conclusions: The web-based intervention was effective for urban, but not rural, participants at 4 months. Rural participants were also less engaged at 4 months, which may explain differences in effectiveness. Technology-based interventions can help address urban-rural disparities in patients with COPD, but may also contribute to them unless resources are available to support engagement with the technology., (© 2023 National Rural Health Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Clinical applications of siRNA therapeutics have been limited by the immunogenicity of the siRNA and low efficiency of siRNA delivery to target cells. Recently, evidence have shown that exosomes, endogenous nanovesicles, can deliver siRNA to the tumor tissues in mice. Here, to reduce immunogenicity, we selected immature dendritic cells (DCs) to produce exosomes. In addition, tumor targeting was achieved by engineering the DCs to express exosomal membrane protein (Lamp2b), fused to av integrin-specific iRGD peptide (CRGDKGPDC). Next, iRGD targeted exosomes (iRGD-Exo) were isolated from the transfected DCs, and then the isolated exosomes were loaded with BCL6 siRNA by electroporation. Our results found that integrin (αvβ3) receptors were highly expressed on OCI-Ly8 cells. In addition, iRGDExo showed high targeting ability with αvβ3 integrins positive OCI-Ly8 cells. Significantly, iRGD-Exo loaded with BCL6 siRNA suppressed DLBCL cell proliferation in vitro. Furthermore, intravenously injected iRGD-Exo delivered BCL6 siRNA to tumor tissues, resulting in inhibition of tumor growth in DLBCL. Meanwhile, exosomes mediated BCL6 siRNA delivery did not exhibit appreciable toxicity in mice. Collectively, our study demonstrates a therapeutic potential of exosomes as a promising vehicle for RNAi delivery to treat DLBCL. [ABSTRACT FROM AUTHOR]

The pathogenesis of neurodegenerative diseases involves the accumulation of misfolded protein aggregates. These deposits are both directly toxic to neurons, invoking loss of cell connectivity and cell death, and recognized by innate sensors that upon activation release neurotoxic cytokines, chemokines, and various reactive species. This neuroinflammation is propagated through signaling cascades where activated sensors/receptors, adaptors, and effectors associate into multiprotein complexes known as supramolecular organizing centers (SMOCs). This review provides a comprehensive overview of the SMOCs, involved in neuroinflammation and neurotoxicity, such as myddosomes, inflammasomes, and necrosomes, their assembly, and evidence for their involvement in common neurodegenerative diseases. We discuss the multifaceted role of neuroinflammation in the progression of neurodegeneration. Recent progress in the understanding of particular SMOC participation in common neurodegenerative diseases such as Alzheimer’s disease offers novel therapeutic strategies for currently absent disease-modifying treatments. [ABSTRACT FROM AUTHOR]

Inhaled treprostinil was approved recently for interstitial lung disease‐pulmonary hypertension; however, efficacy in "real‐world" populations is not known. We designed a protocol and report our experience evaluating 10 patients referred for therapy. Misdiagnosis at presentation was common; ultimately, three patients (30%) were prescribed drug. This protocol offers an opportunity to standardize longitudinal assessment of inhaled treprostinil in clinical practice. [ABSTRACT FROM AUTHOR]

Copyright of AIDS & Behavior is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Serial criminality, although rare, has always aroused the interest of researchers in criminology, psychiatry, psychology, and sociology. We report the case of a patient, suffering from a chronic psychotic disorder, having committed several murders over a period of 9 years, underpinned by a delirium of misidentification of Frigoli syndrome. [ABSTRACT FROM AUTHOR]

Background: Ionizing radiation (IR) can induce pulmonary fibrosis by causing epithelial mesenchymal transition (EMT), but the exact mechanism has not been elucidated. To investigate the molecular mechanism of how radiation induces pulmonary fibrosis by altering miR-486-3p content and thus inducing EMT.Methods: The changes of miR-486-3p in cells after irradiation were detected by RT-qPCR. Western blot was used to detect the changes of cellular epithelial marker protein E-cadherin, mesenchymal marker N-cadherin, Vimentin and other proteins. The target gene of miR-486-3p was predicted by bioinformatics method and the binding site was verified by dual luciferase reporter system. In vivo experiments, adeno-associated virus (AAV) was used to carry miR-486-3p mimic to lung. Radiation-induced pulmonary fibrosis (RIPF) model was constructed by 25Gy60Co γ-rays. The structural changes of mouse lung were observed by HE and Masson staining. The expression of relevant proteins in mice was detected by immunohistochemistry.Results: IR could decrease the miR-486-3p levels in vitro and in vivo, and that effect was closely correlated to the occurrence of RIPF. The expression of Snail, which induces EMT, was shown to be restrained by miR-486-3p. Therefore, knockdown of Snail blocked the EMT process induced by radiation or knockdown of miR-486-3p. In addition, the molecular mechanism underlying the IR-induced miRNA level reduction was explored. The increased in BCL6 could inhibit the formation of pri-miR-486-3p, thereby reducing the levels of miR-486-3p in the alveolar epithelial cells, which would otherwise promote EMT and contribute to RIPF by targeting Snail.Conclusion: IR can exacerbate RIPF in mice by activating the transcription factor BCL6, which inhibits the transcription of miR-486-3p and decreases its content, which in turn increases the content of the target gene slug and triggers EMT. [ABSTRACT FROM AUTHOR]

Summary: Human T cell leukemia virus type 1 (HTLV-1) is responsible for adult T cell leukemia (ATL); however, molecular and cellular mechanisms underlying HTLV-1-induced leukemogenesis are unclear. BCL6 oncogene is involved in cancer progression and a preferred target of anti-cancer treatments. Here, we aimed to evaluate BCL6 expression and the effects of BCL6 inhibitor (FX1) on HTLV-1-infected T cell lines. BCL6 expression was higher in HTLV-1-infected T cell lines than that in uninfected T cell lines. BCL6 was localized mostly in the nucleus. The virus oncoprotein Tax induced BCL6 mRNA expression in T cells, whereas BCL6 knockdown reduced HTLV-1-infected T cell proliferation; thus, confirmed the association of BCL6 with cancer progression. Further, FX1 efficiently inhibited the cell growth and survival of HTLV-1-infected T cell lines in a dose- and time-dependent manner. The decreased levels of cell cycle regulatory proteins (phosphorylated retinoblastoma protein, cyclin-dependent kinase 4, cyclin D2 and c-Myc) and the increased levels of BCL6 target proteins (p21, p27 and p53) showed that FX1 arrested cell cycle at the G1 phase. Apoptosis was induced concomitantly with Bak upregulation and downregulation of survivin, Bcl-xL and Mcl-1, as well as with the activation of caspase-3, -8, -9 and poly(ADP-ribose) polymerase. FX1 also inhibited NF-κB and Akt signaling pathways. These events were because of the induction of the activity of cell cycle checkpoint proteins and relief of direct repression of the targets of cell cycle checkpoint proteins. Thus, BCL6 might be considered a novel target for ATL treatment. [ABSTRACT FROM AUTHOR]

Background: The transcriptional repressor B-cell lymphoma 6 (BCL6) is dysregulated in several neoplasms, but its role in triple negative breast cancer (TNBC), a highly aggressive subtype which lacks effective treatment, is unclear. The presence of intratumoral cancer stem cells (CSCs) is a main cause of tumor relapse. The Notch signaling pathway is crucial for regulating CSC self-renewal and promoting breast cancer (BC) development and resistance to anticancer therapies. Here, we investigated signaling cascades of BCL6 in the CSC compartment of TNBCs, and the mechanisms that govern its activity, mainly through Notch signaling. Methods: Gene expression, somatic copy number alterations and clinical data from the Cancer Genome Atlas and METABRIC were accessed through the Xena and cbioportal browsers. Public transcriptome profiles from TNBC datasets were retrieved from the Gene Expression Omnibus. Mammosphere formation efficiency was calculated after BCL6 knockdown via transient siRNA transfection, stable silencing or pharmacological inhibition. The effects exhibited via BCL6 inhibition in putative TNBC stem-like cells were evaluated by immunofluorescence and qRT-PCR analyses. Chromatin immunoprecipitation experiments were performed to validate a putative BCL6 responsive element located in the first intron of the Numb gene and to define the circuit of corepressors engaged by BCL6 following its inhibition. Immunoprecipitation assays were carried out to investigate a novel interaction at the basis of BCL6 control of CSC activity in TNBC. Results: In silico analyses of benchmarked public datasets revealed a significant enrichment of BCL6 in cancer stemness related pathways, particularly of Notch signaling in TNBC. In vitro stable inhibition of BCL6 significantly reduced tumor cell growth and, accordingly, we found that the mammosphere formation efficiency of BCL6 silenced cells was significantly impaired by pharmacological inhibition of Notch signaling. BCL6 was found to be expressed at significantly higher levels in TNBC mammospheres than in their adherent counterparts, and loss of BCL6 function significantly decreased mammosphere formation with preferential targeting of CD44-positive versus ALDH-positive stem-like cells. Functional interplay between BCL6 and the chromatin remodeling factor EZH2 triggered the BCL6/Notch stemness signaling axis via inhibition of Numb transcription. Conclusions: Our results may be instrumental for the prospective design of combination treatment strategies that selectively target novel TNBC-associated biomarker(s) whose activity is implicated in the regulation of cancer stemness (such as BCL6) and molecules in developmentally conserved signaling pathways (such as Notch) to achieve long-lasting tumor control and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Type I interferon (IFN) has been identified in patients with Lyme disease, and its abundant expression in joint tissues of C3H mice precedes development of Lyme arthritis. Forward genetics using C3H mice with severe Lyme arthritis and C57BL/6 (B6) mice with mild Lyme arthritis identified the Borrelia burgdorferi arthritis-associated locus 1 (Bbaa1) on chromosome 4 (Chr4) as a regulator of B. burgdorferi-induced IFNβ expression and Lyme arthritis severity. B6 mice introgressed with the C3H allele for Bbaa1 (B6.C3-Bbaa1 mice) displayed increased severity of arthritis, which is initiated by myeloid lineage cells in joints. Using advanced congenic lines, the physical size of the Bbaa1 interval has been reduced to 2 Mbp, allowing for identification of potential genetic regulators. Small interfering RNA (siRNA)-mediated silencing identified Cdkn2a as the gene responsible for Bbaa1 allele-regulated induction of IFNβ and IFN-stimulated genes (ISGs) in bone marrow-derived macrophages (BMDMs). The Cdkn2a-encoded p19 alternative reading frame (p19ARF) protein regulates IFNβ induction in BMDMs as shown by siRNA silencing and overexpression of ARF. In vivo studies demonstrated that p19ARF contributes to joint-specific induction of IFNβ and arthritis severity in B. burgdorferi-infected mice. p19ARF regulates B. burgdorferi-induced IFNβ in BMDMs by stabilizing the tumor suppressor p53 and sequestering the transcriptional repressor BCL6. Our findings link p19ARF regulation of p53 and BCL6 to the severity of IFNβ-induced Lyme arthritis in vivo and indicate potential novel roles for p19ARF, p53, and BCL6 in Lyme disease and other IFN hyperproduction syndromes. Author summary: Lyme disease is caused by infection with the tick-transmitted bacterium Borrelia burgdorferi. Although different isolates of B. burgdorferi have distinct potential for dissemination and tissue invasion, factors intrinsic to the infected host also play an important role in directing the severity of Lyme disease. In the animal model, infected C3H mice develop severe Lyme arthritis following elevation of type I IFN in joint tissue, while in C57BL/6 (B6) mice arthritis is mild and not associated with type I IFN. We demonstrated that the Borrelia burgdorferi arthritis-associated locus 1 (Bbaa1) on chromosome 4 (Chr4) intrinsically controls the magnitude of IFNβ production and the severity of Lyme arthritis in C3H vs B6 mice. The Cdkn2a gene was positionally identified as the regulator of IFNβ within Bbaa1, and determined to function through its protein product p19 alternative reading frame (p19ARF). ARF regulates IFNβ expression and Lyme arthritis severity by modulating the activities of the tumor suppressor p53 and transcriptional repressor BCL6. Our study provides new insight and potential therapeutic targets for the investigation of type I IFN-dependent Lyme arthritis and other IFN-driven diseases. [ABSTRACT FROM AUTHOR]

Objective Determine the relationship characteristics, sexual health attitudes, and demographic factors associated with dual contraceptive use among college students. Participants: September–October 2018 via campus email, we recruited College of Public Health students attending a large, urban, public university (N = 424). Methods: Respondents completed a cross-sectional, Web-based sexual health questionnaire. Descriptive statistics were calculated. Multiple logistic regression models were run to determine the association between relationship characteristics, pregnancy and condom attitudes, demographics, and dual use the last time having sex. Results: In independent models, one-unit increase in trust (aOR = 0.982; 95% CI: 0.966–0.998) and commitment score (aOR = 0.987, 95% CI: 0.976–0.999) was inversely associated with dual use while sex with a casual date/acquaintance (aOR = 3.149; 95% CI: 1.550–6.397) was positively associated. In a fully adjusted model for all correlates, only trust score was significant (aOR = 0.982; 95% CI: 0.966, 0.998). Conclusions: Emotion-based constructs may be more influential on dual use behaviors than discrete relationship factors. [ABSTRACT FROM AUTHOR]

The co-occurrence of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) in the same patient, named the overlap syndrome (OS), was first described in 1985. Although the American Thoracic Society underlined the limited knowledge of OS, stated research priorities for this condition, and recommended a "screening" strategy to identify OSA in COPD patients with chronic stable hypercapnia, research studies on OS remain scarce. This review aims to summarize the current knowledge and perspectives related to OSA in COPD patients. OS prevalence is 1.0–3.6% in the general population, 3–66% in COPD patients, and 7–55% in OSA patients. OS patients may have worse sleep quality than those with OSA or COPD alone. Scoring hypopneas may be difficult in COPD patients; desaturation episodes may have origins in these patients, namely upper airway obstruction, hypoventilation during paradoxical sleep, ventilation/perfusion mismatches, and obesity. The apnea–hypopnea index is similar in OSA and OS patients. Desaturations may be greater and more prolonged in OS patients than in patients with COPD or OSA alone. Low body mass index, hyperinflation, and less collapsible airways reduce the risk of OSA in COPD patients. OSA is a risk factor for pulmonary hypertension in COPD patients. Whether OS increases mortality and morbidity risks compared to COPD or OSA alone remains to be confirmed. No guidelines currently recommend specific approaches to the treatment of OSA in patients with COPD. [ABSTRACT FROM AUTHOR]

Copyright of Gazi Medical Journal is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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The Supreme Court ruling in Dobbs v. Jackson Women's Health Organization has far-reaching implications that go beyond the practice of obstetrics and gynecology. The ruling and subsequent laws and bills impact many specialties and have implications for healthcare as a whole. The rapidly changing medicolegal landscape has significant bearings on and implications for the fields of neonatology and pediatrics. These rulings have an impact on the patient-physician relationship and a shared decision-making approach to care. Furthermore, there are significant sequelae of forced birth and resuscitation. This review provides a clinically relevant update of the current medicolegal landscape and applications to the practice of neonatology., (© 2022. The Author(s).)

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48-250 µg/kg tested to date (n = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6-56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2-27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Over the last decades, the revolution in DNA sequencing has changed the way we understand the genetics and biology of B-cell lymphomas by uncovering a large number of recurrently mutated genes, whose aberrant function is likely to play an important role in the initiation and/or maintenance of these cancers. Dissecting how the involved genes contribute to the physiology and pathology of germinal center (GC) B cells –the origin of most B-cell lymphomas– will be key to advance our ability to diagnose and treat these patients. Genetically engineered mouse models (GEMM) that faithfully recapitulate lymphoma-associated genetic alterations offer a valuable platform to investigate the pathogenic roles of candidate oncogenes and tumor suppressors in vivo , and to pre-clinically develop new therapeutic principles in the context of an intact tumor immune microenvironment. In this review, we provide a summary of state-of-the art GEMMs obtained by accurately modelling the most common genetic alterations found in human GC B cell malignancies, with a focus on Burkitt lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma, and we discuss how lessons learned from these models can help guide the design of novel therapeutic approaches for this disease. [ABSTRACT FROM AUTHOR]

Lymphomas are cancers deriving from lymphocytes, arising preferentially in secondary lymphoid organs, and represent the 6th cancer worldwide and the most frequent blood cancer. The majority of B cell Non-Hodgkin lymphomas (B-NHL) develop from germinal center (GC) experienced mature B cells. GCs are transient structures that form in lymphoid organs in response to antigen exposure of naive B cells, and where B cell receptor (BCR) affinity maturation occurs to promote B cell differentiation into memory B and plasma cells producing high-affinity antibodies. Genomic instability associated with the somatic hypermutation (SHM) and class-switch recombination (CSR) processes during GC transit enhance susceptibility to malignant transformation. Most B cell differentiation steps in the GC are at the origin of frequent B cell malignant entities, namely Follicular Lymphoma (FL) and GCB diffuse large B cell lymphomas (GCB-DLBCL). Over the past decade, large sequencing efforts have provided a great boost in the identification of candidate oncogenes and tumor suppressors involved in FL and DLBCL oncogenesis. Mouse models have been instrumental to accurately mimic in vivo lymphoma-specific mutations and interrogate their normal function in the GC context and their oncogenic function leading to lymphoma onset. The limited access of biopsies during the initiating steps of the disease, the cellular and (epi)genetic heterogeneity of individual tumors across and within patients linked to perturbed dynamics of GC ecosystems make the development of genetically engineered mouse models crucial to decipher lymphomagenesis and disease progression and eventually to test the effects of novel targeted therapies. In this review, we provide an overview of some of the important genetically engineered mouse models that have been developed to recapitulate lymphoma-associated (epi)genetic alterations of two frequent GC-derived lymphoma entities: FL and GCB-DLCBL and describe how those mouse models have improved our knowledge of the molecular processes supporting GC B cell transformation. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer (PC) is a highly fatal and aggressive disease with its incidence and mortality quite discouraging. An effective prediction model is urgently needed for the accurate assessment of patients' prognosis to assist clinical decision-making. Methods: Gene expression data and clinicopathological data of the samples were acquired from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases. Differential expressed genes (DEGs) analysis, univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression analysis, random forest screening and multivariate Cox regression analysis were applied to construct the risk signature. The effectiveness and independence of the model were validated by time-dependent receiver operating characteristic (ROC) curve, Kaplan–Meier (KM) survival analysis and survival point graph in training set, test set, TCGA entire set and GSE57495 set. The validity of the core gene was verified by immunohistochemistry and our own independent cohort. Meanwhile, functional enrichment analysis of DEGs between the high and low risk groups revealed the potential biological pathways. Finally, CMap database and drug sensitivity assay were utilized to identify potential small molecular drugs as the risk model-related treatments for PC patients. Results: Four histone modification-related genes were identified to establish the risk signature, including CBX8, CENPT, DPY30 and PADI1. The predictive performance of risk signature was validated in training set, test set, TCGA entire set and GSE57495 set, with the areas under ROC curve (AUCs) for 3-year survival were 0.773, 0.729, 0.775 and 0.770 respectively. Furthermore, KM survival analysis, univariate and multivariate Cox regression analysis proved it as an independent prognostic factor. Mechanically, functional enrichment analysis showed that the poor prognosis of high-risk population was related to the metabolic disorders caused by inadequate insulin secretion, which was fueled by neuroendocrine aberration. Lastly, a cluster of small molecule drugs were identified with significant potentiality in treating PC patients. Conclusions: Based on a histone modification-related gene signature, our model can serve as a reliable prognosis assessment tool and help to optimize the treatment for PC patients. Meanwhile, a cluster of small molecule drugs were also identified with significant potentiality in treating PC patients. [ABSTRACT FROM AUTHOR]

Mouse models of human cancer provide an important research tool for elucidating the natural history of neoplastic growth and developing new treatment and prevention approaches. This is particularly true for multiple myeloma (MM), a common and largely incurable neoplasm of post-germinal center, immunoglobulin-producing B lymphocytes, called plasma cells, that reside in the hematopoietic bone marrow (BM) and cause osteolytic lesions and kidney failure among other forms of end-organ damage. The most widely used mouse models used to aid drug and immunotherapy development rely on in vivo propagation of human myeloma cells in immunodeficient hosts (xenografting) or myeloma-like mouse plasma cells in immunocompetent hosts (autografting). Both strategies have made and continue to make valuable contributions to preclinical myeloma, including immune research, yet are ill-suited for studies on tumor development (oncogenesis). Genetically engineered mouse models (GEMMs), such as the widely known Vκ*MYC, may overcome this shortcoming because plasma cell tumors (PCTs) develop de novo (spontaneously) in a highly predictable fashion and accurately recapitulate many hallmarks of human myeloma. Moreover, PCTs arise in an intact organism able to mount a complete innate and adaptive immune response and tumor development reproduces the natural course of human myelomagenesis, beginning with monoclonal gammopathy of undetermined significance (MGUS), progressing to smoldering myeloma (SMM), and eventually transitioning to frank neoplasia. Here we review the utility of transplantation-based and transgenic mouse models of human MM for research on immunopathology and -therapy of plasma cell malignancies, discuss strengths and weaknesses of different experimental approaches, and outline opportunities for closing knowledge gaps, improving the outcome of patients with myeloma, and working towards a cure. [ABSTRACT FROM AUTHOR]

Harnessing the power of immune cells, especially T cells, to enhance anti-tumor activities has become a promising strategy in clinical management of hematologic malignancies. The emerging bispecific antibodies (BsAbs), which recruit T cells to tumor cells, exemplified by bispecific T cell engagers (BiTEs), have facilitated the development of tumor immunotherapy. Here we discussed the advances and challenges in BiTE therapy developed for the treatment of hematologic malignancies. Blinatumomab, the first BiTE approved for the treatment of acute lymphocytic leukemia (ALL), is appreciated for its high efficacy and safety. Recent studies have focused on improving the efficacy of BiTEs by optimizing treatment regimens and refining the molecular structures of BiTEs. A considerable number of bispecific T cell-recruiting antibodies which are potentially effective in hematologic malignancies have been derived from BiTEs. The elucidation of mechanisms of BiTE action and neonatal techniques used for the construction of BsAbs can improve the treatment of hematological malignancies. This review summarized the features of bispecific T cell-recruiting antibodies for the treatment of hematologic malignancies with special focus on preclinical experiments and clinical studies. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (AMI) and the following heart failure are public health problems faced all over the globe. The current study set out to investigate the role of B‐cell lymphoma 6 (BCL‐6) in cardiac protection after AMI. Initially, AMI mouse models and H9c2 cell oxygen–glucose deprivation (OGD) models were established. The cell models were transfected with the vectors containing oe‐BCL‐6, oe‐EZH2, sh‐EZH2, miR‐34a mimic, and miR‐34a inhibitor. RT‐qPCR and Western blot analysis were applied to detect the expression patterns of microRNA‐34a (miR‐34a), BCL‐6, enhancer of zeste homolog 2 (EZH2), and C1q tumor necrosis factor‐related protein 9 (CTRP9) in the treated cell models. ChIP‐qPCR and co‐immunoprecipitation assay were performed to detect EZH2 enrichment and H3K27me3 levels in the miR‐34a promoter region and the interaction between BCL‐2 and EZH2, respectively. EdU staining, TUNEL staining, and flow cytometry were performed to detect cell proliferation and apoptosis, while ELISA was conducted to detect the oxidative stress levels. It was found that miR‐34a was highly expressed in heart tissues of AMI models, while BCL‐6 and EZH2 were poorly expressed. BCL‐2 overexpression increased the recruitment of EZH2, upregulated H3K27me3 level in the miR‐34a promoter region, and inhibited the miR‐34a expression. Ctrp9, the downstream negative‐regulatory molecule of miR‐34a, was upregulated. Besides, miR‐34a/CTRP9 expression changes were found to affect cardiomyocyte apoptosis, oxidation stress, and proliferation, and prevent myocardial injury in AMI mice. Our findings indicate that BCL‐6 increases the level of H3K27me3 in the promoter region of miR‐34a via EZH2 recruitment and CTRP9 upregulation, which inhibits the apoptosis of myocardial cells. [ABSTRACT FROM AUTHOR]