NF-κB plays an important role in cancer initiation and progression. CD44, a cell surface glycoprotein, is involved in many cellular processes including cell adhesion, migration and proliferation. ...However, whether and how the two molecules interact in breast cancer is not clear. In recent years, the up-regulation of CD44 has served as a marker for tumor initiating cells in breast cancer and other cancer types. Despite the important role of CD44 in cellular processes and cancer, the mechanism underlying CD44 up-regulation in cancers remains poorly understood. Previously, we have identified a novel cis-element, CR1, located upstream of the CD44 promoter. We demonstrated that NF-κB and AP-1 are key trans-acting factors that interact with CR1. Here, we further analyzed the role of NF-κB in regulating CD44 expression in triple negative breast cancer cells, MDA-MB-231 and SUM159. Inhibition of NF-κB by Bay-11-7082 resulted in a reduction in CD44 expression. CD44 repression via NF-κB inhibition consequently decreased proliferation and invasiveness of breast cancer cells. These findings provide not only new insight into the molecular mechanism underlying CD44 regulation but also potential therapeutic targets that may help eliminate chemo- and radiation-resistant cancer cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The objective of the study was to synthesize the epidemiological findings for the associations between dysmenorrhea, including primary dysmenorrhea and endometriosis-associated dysmenorrhea and any ...chronic pain conditions, including chronic pelvic pain, and chronic nonpelvic pain.
The data sources included PubMed, Embase, and CINAHL from inception to December 2019.
The study criteria included observational population-based studies in which the relationship between dysmenorrhea and the presence or severity of chronic pain was examined.
Each study was double coded and evaluated for bias based on the modified Newcastle and Ottawa Scale. Random-effect meta-analyses were conducted to quantify the associations between dysmenorrhea and the presence of chronic pelvic and nonpelvic pain.
Out of 9452 records, 32 studies were included, with 14 reporting associations between dysmenorrhea and chronic pelvic pain, and 20 for dysmenorrhea and chronic nonpelvic pain. Primary dysmenorrhea and endometriosis-associated dysmenorrhea were examined in 7 studies, respectively. More than 30% of the studies were categorized as poor quality, 56% as moderate, and 12.5% as high. Dysmenorrhea was positively associated with both the presence and severity of chronic pelvic and nonpelvic pain conditions. Based on 6689 women from 8 studies, those with chronic pelvic pain had 2.43 (95% confidence interval, 1.98–2.99, I2, 42%) times the odds of having dysmenorrhea compared with those without. Based on 3750 women from 11 studies, those with chronic nonpelvic pain had 2.62 (95% confidence interval, 1.84–3.72, I2, 72%) times the odds of having dysmenorrhea compared with those without. Overall, dysmenorrhea was associated with 2.50 (95% confidence interval, 2.02–3.10) times the odds of chronic pain, which did not differ by chronic pelvic vs chronic nonpelvic pain, community vs clinical populations, or different geographical regions.
Dysmenorrhea may be a general risk factor for chronic pain, although whether primary dysmenorrhea increases the risk for chronic pain is unclear. Given that adolescence is a sensitive period for neurodevelopment, elucidating the role of primary dysmenorrhea in pain chronicity in future longitudinal studies is important for preventing both chronic pelvic and nonpelvic pain.
Leukemia stem cells (LSCs) are thought to drive the genesis of acute myeloid leukemia (AML) as well as relapse following chemotherapy. Because of their unique biology, developing effective methods to ...eradicate LSCs has been a significant challenge. In the present study, we demonstrate that intrinsic overexpression of the mitochondrial dynamics regulator FIS1 mediates mitophagy activity that is essential for primitive AML cells. Depletion of FIS1 attenuates mitophagy and leads to inactivation of GSK3, myeloid differentiation, cell cycle arrest, and a profound loss of LSC self-renewal potential. Further, we report that the central metabolic stress regulator AMPK is also intrinsically activated in LSC populations and is upstream of FIS1. Inhibition of AMPK signaling recapitulates the biological effect of FIS1 loss. These data suggest a model in which LSCs co-opt AMPK/FIS1-mediated mitophagy as a means to maintain stem cell properties that may be otherwise compromised by the stresses induced by oncogenic transformation.
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•Human AML LSCs display high FIS1 expression and unique mitochondrial morphology•FIS1 loss attenuates mitophagy and impairs AML LSC potential•FIS1 loss induces GSK3 inhibition, differentiation, and cell cycle arrest in AML•AMPK is constitutively active in human AML LSCs and regulates FIS1 expression
Human acute myeloid leukemia stem cells (LSCs) depend on FIS1-mediated mitophagy for self-renewal and survival. AMPK is constitutively active in human LSCs, is upstream of FIS1, and acts to stimulate mitophagy. Disruption of AMPK signaling or FIS1 activity results in eradication of LSCs.
Revisions to the posttraumatic stress disorder (PTSD) criteria in the DSM-5 included a new criterion in the alterations in arousal and reactivity cluster (i.e., engagement in reckless and ...self-destructive behaviors; Criterion E2). Despite its clinical significance, little is known about how this symptom corresponds to engagement in specific direct and indirect self-harm behaviors. We examined associations between E2 and self-reported recent engagement in direct and indirect self-harm behaviors, including disordered eating, which is not included in the prototypical E2 symptom scope, in a trauma-exposed sample of 1,010 recent-era veterans (61.5% self-identified women, 38.5% self-identified men). We also tested whether gender moderated these associations. We repeated analyses in a subsample of participants with clinically elevated PTSD symptoms. Participants self-reported past-month PTSD symptoms (PCL-5) as well as past-month nonsuicidal self-injury, suicidal ideation, suicide planning, fasting, purging, binge eating, compulsive exercise, and problematic alcohol and drug use. We found no evidence for moderation by gender for any of the behaviors examined in the main sample. However, after controlling for gender and demographic covariates, weighted logistic regressions showed small, significant associations between E2 score and direct self-harm behaviors, substance use, purging, and binge eating, aORs = 1.30-1.91. Criterion E2 was linked to behaviors included in the typical symptom scope (self-directed violence, substance use) and those that are not (disordered eating behaviors). Comprehensive screening for self-destructive behaviors, including disordered eating, among veteran men and women who endorse Criterion E2 is indicated.
Cognitive processing therapy (CPT) is an evidence‐based treatment for posttraumatic stress disorder (PTSD), but little is known about in‐session process variables that predict symptom reduction and ...treatment completion during CPT. Examining potentially malleable factors that may promote or impede recovery can inform care delivery and enhance outcomes. The current study used observational ratings of CPT session recordings to examine in‐session patient and therapist factors in cognitive, affective, and interpersonal domains to identify their relative contributions to predicting symptom outcomes and treatment completion. Participants were 70 adult survivors of interpersonal violence who received CPT. Predictors of better posttreatment PTSD outcomes included less patient fear, β = .32, and less patient avoidance of engaging with the therapist, β = .35. When using the last available PTSD score, less fear, β = .23, and avoidance, β = .28, continued to predict better outcomes, and more patient cognitive flexibility emerged as a stronger predictor of outcome, β = ‐.33. Predictors of a higher likelihood of treatment completion included more therapist use of Socratic dialogue, OR = 6.75, and less therapist encouragement of patient affect, OR = 0.11. Patient sadness and anger and therapist expression of empathy did not predict symptom outcomes or treatment completion versus dropout. The results highlight the importance of patients’ cognitions, emotions, and engagement with their therapist in CPT as well as the role of therapist behaviors in patient completion of treatment.
Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and ...effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.
Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, ...Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.
There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to ...calls for "precision medicine" or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.
Breast cancers contain a heterogeneous population of cells with a small percentage that possess properties similar to those found in stem cells. One of the widely accepted markers of breast cancer ...stem cells (BCSCs) is the cell surface marker CD44. As a glycoprotein, CD44 is involved in many cellular processes including cell adhesion, migration and proliferation, making it pro-oncogenic by nature. CD44 expression is highly up-regulated in BCSCs, and has been implicated in tumorigenesis and metastasis. However, the genetic mechanism that leads to a high level of CD44 expression in breast cancer cells and BCSCs is not well understood. Here, we identify a novel cis-element of the CD44 directs gene expression in breast cancer cells in a cell type specific manner. We have further identified key trans-acting factor binding sites and nuclear factors AP-1 and NFκB that are involved in the regulation of cell-specific CD44 expression. These findings provide new insight into the complex regulatory mechanism of CD44 expression, which may help identify more effective therapeutic targets against the breast cancer stem cells and metastatic tumors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To assess the reported changes in orgasm quality and function of transgender men (TM) and transgender women (TW) after commencing gender-affirming hormone therapy (GAHT).
We queried potential changes ...in orgasm function before and after commencing GAHT (minimum 1 year) among 130 consecutive TW and 33 TM. We queried the following domains under a uniform condition (masturbation): (1) Lead-time to reach orgasm, (2) Duration of orgasm, (3) Body location of orgasm sensation, (4) Description of orgasm as either a single or multiple-peak event, (5) Duration of post-orgasm refractory period, and (6) Overall satisfaction with orgasm quality.
Within groups by gender, TW and TM reported similar responses to our inventory before starting GAHT. After commencing GAHT, TW reported notable changes in orgasm function: increase in lead-time necessary to reach orgasm, orgasm duration, and overall orgasm satisfaction. Similarly, TM reported an increase in duration of orgasm and increased overall satisfaction with orgasm quality.
Over half of the TW reported experiencing orgasms in new/additional body locations. Additionally, prior to commencing GAHT, the majority of TM and TW patients reported their orgasms as a short, single-peak event but following GAHT these same patients reported longer and protracted multiple-peak orgasms.
GAHT has the potential to positively improve orgasm quality for transgender patients undergoing gender transition. It is important to share such data with patients prospectively before treatments.
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