The gut microbiota is essential for maintenance and repair of the intestinal epithelial barrier. As shifts in both intestinal epithelial barrier function and microbiota composition are found in inflammatory bowel disease patients, it is critical to understand the role of distinct bacteria in regulating barrier repair. We identified a mouse commensal E. coli isolate, GDAR2-2, that protects mice from Citrobacter rodentium infection and dextran sulfate sodium-induced colitis. Colonization with GDAR2-2 in mice resulted in expansion of CX3CR1⁺ mononuclear phagocytes, including CX3CR1⁺ macrophages/dendritic cells and monocytes, along with IL-22-secreting type 3 innate lymphoid cells and improved epithelial barrier function. In vitro co-culture of macrophages with GDAR2-2 resulted in IL-1β production. In vivo, protection after GDAR2-2 colonization was lost after depletion of CX3CR1⁺ MNPs, or blockade of IL-1β or IL-22. We further identified human commensal E. coli isolates that similarly protect mice from C. rodentium infection through CX3CR1⁺ MNP and IL-1β production. Together, these findings demonstrate an unexpected role for commensal bacteria in promoting IL-1β secretion to support intestinal barrier repair.
Colon tumors with deficient DNA mismatch repair (dMMR) are generally infiltrated by T cells more densely than tumors with proficient mismatch repair (pMMR). However, high numbers of tumor-infiltrating lymphocytes (TILs) are found in select pMMR tumors, and low numbers of TILs are seen in select dMMR tumors. In this study, we compared T-cell repertoires in 20 pMMR and 27 dMMR colon tumors with high and low TIL counts. We found that T cells in dMMR tumors are more clonal and their repertoire is less rich compared with T cells in pMMR tumors. In the dMMR group, T cells in TIL-high tumors were more clonal and their repertoire was less rich compared with T cells in TIL-low tumors, but in the pMMR group, T-cell diversity in TIL-high tumors was comparable to T-cell diversity in TIL-low tumors. These findings suggest that T cells clonally expand in dMMR tumors, possibly in response to MMR deficiency-induced tumor neoantigens.
Microwave ablation (MWA) is becoming an increasingly important minimally invasive treatment option for localized tumors in many organ systems due to recent advancements in microwave technology that have conferred many advantages over other tumor ablation modalities. Despite these improvements in technology and development of applicators for site-specific tumor applications, the vast majority of commercially available MWA applicators are generally designed to create large-volume, symmetric, ellipsoid or spherically-shaped treatment zones and often lack the consistency, predictability, and spatial control needed to treat tumor targets near critical structures that are vulnerable to inadvertent thermal injury. The relatively new development and ongoing translation of directional microwave ablation (DMWA) technology, however, has the potential to confer an added level of control over the treatment zone shape relative to applicator position, and shows great promise to expand MWA's clinical applicability in treating tumors in challenging locations. This paper presents a review of the industry-standard commercially available MWA technology, its clinical applications, and its limitations when used for minimally-invasive tumor treatment in medical practice followed by discussion of new advancements in experimental directional microwave ablation (DMWA) technology, various techniques and approaches to its use, and examples of how this technology may be used to treat tumors in challenging locations that may otherwise preclude safe treatment by conventional omni-directional MWA devices.
Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Alzheimer’s disease (AD) is the most common type of neurodegenerative disorder. Amyloid-beta (Aβ) plaques are integral to the “amyloid hypothesis,” which states that the accumulation of Aβ peptides triggers a cascade of pathological events leading to neurodegeneration and ultimately AD. While the FDA approved aducanumab, the first Aβ-targeted therapy, multiple safe and effective treatments will be needed to target the complex pathologies of AD. γ-Secretase is an intramembrane aspartyl protease that is critical for the generation of Aβ peptides. Activity and specificity of γ-secretase are regulated by both obligatory subunits and modulatory proteins. Due to its complex structure and function and early clinical failures with pan inhibitors, γ-secretase has been a challenging drug target for AD. γ-secretase modulators, however, have dramatically shifted the approach to targeting γ-secretase. Here we review γ-secretase and small molecule modulators, from the initial characterization of a subset of NSAIDs to the most recent clinical candidates. We also discuss the chemical biology of γ-secretase, in which small molecule probes enabled structural and functional insights into γ-secretase before the emergence of high-resolution structural studies. Finally, we discuss the recent crystal structures of γ-secretase, which have provided valuable perspectives on substrate recognition and molecular mechanisms of small molecules. We conclude that modulation of γ-secretase will be part of a new wave of AD therapeutics.
Mobile mammography vans (mammovans) may help close the gap to access of breast cancer screening by providing resources to underserved communities. Minimal data exists on the populations served, the ability of mammovans to reach underserved populations, and the outcomes of participants. We sought to determine the demographic characteristics, number of breast cancers diagnosed, and number of women who used the American Italian Cancer Foundation (AICF) Mobile, No-Cost Breast Cancer Screening Program within the five boroughs of New York City. Data were collected by the AICF from 2014 to 2019 on a voluntary basis from participants at each screening location. Women aged 40 to 79 years who had not had a mammogram in the previous 12 months were invited to participate. Each participant underwent a clinical breast exam by a nurse practitioner followed by a screening mammogram. Images were read by a board-certified radiologist contracted by the AICF from Multi Diagnostic Services. There were 32,350 participants in this study. Sixty-three percent reported an annual household income ≤$25,000, and 30% did not have health insurance. More than half of participants identified as either African American (28%) or Hispanic (27%). Additional testing was performed for 5359 women found to have abnormal results on screening. In total, 68 cases of breast cancer were detected. Breast cancer disparities are multifactorial, with the greatest factor being limited access to care. Mobile, no-cost mammogram screening programs show great promise in helping to close the gap to screening access.
Identification of recurrent mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) in patients with acute myeloid leukemia (AML) coupled with an understanding of the pathologic role these mutant IDH isoforms impart in leukemogenesis resulted in the development of IDH1 and IDH2 inhibitors comprising a novel, molecularly defined class of targeted therapies for the treatment of AML. This review herein describes the unique cellular pathophysiology and vulnerabilities in IDH-mutated AML; the clinical development, efficacy, and known resistance mechanisms to first-generation IDH inhibitors; summarizes the literature surrounding combination therapies incorporating targeted or cytotoxic therapies with IDH inhibitors in patients with IDH-mutated AML; and identifies future challenges and areas of active ongoing investigation within this molecular subgroup.
Increased trunk fat is associated with an elevated risk of breast cancer in normal-weight postmenopausal women. The main objective of this study was to determine whether levels of trunk fat are associated with changes in breast gene expression in normal-weight women. Non-tumorous breast tissue was collected from 32 normal BMI women who underwent mastectomy for breast cancer risk reduction or treatment. Body composition was measured by dual-energy x-ray absorptiometry. High levels of trunk fat were associated with a large number of differentially expressed genes and changes in multiple pathways and processes potentially linked to breast cancer pathogenesis. High levels of trunk fat were also associated with an elevated immune score and increased levels of leptin, CCL2 , VEGF-C , IL6 , and aromatase. Collectively, these results help to explain why high levels of trunk fat are associated with an increased risk of breast cancer in normal BMI women.
Estrogen may have opposing effects on health, namely increasing the risk of breast cancer and improving bone health by increasing bone mineral density (BMD). The objective of this study was to compare dual-energy X-ray absorptiometry (DXA) BMD between women newly diagnosed with breast cancer and matched controls without breast cancer. Women newly diagnosed with breast cancer treated between April 2012 and October 2017 were prospectively enrolled. A control group was established of women with negative mammography or breast ultrasound, matched 1:1 by age, body mass index, parity, and the use of hormone replacement therapy. All those included had DXA BMD, and lab assessments at enrollment. Of 869 women with newly diagnosed breast cancer, 464 signed informed consent. Of the 344 who completed the study protocol, 284 were matched to controls. Overall, the mean age was 58 years. Compared to the control group, for the breast cancer group, the mean vitamin D level was lower (48.9 ± 19.0 vs. 53.8 ± 28.8 nmol/L, p = 0.022); and mean values were higher of total hip BMD (0.95 ± 0.14 vs. 0.92 ± 0.12 g/cm ² , p = 0.002), T score (−0.38 ± 1.17 vs. −0.68 ± 0.98, p = 0.002), and Z score (0.32 ± 1.09 vs. 0.01 ± 0.88, p < 0.001). Among the women with breast cancer, no correlations were found of baseline BMD with tumor size or grade, nodal involvement, or breast cancer stage. We concluded that women with newly diagnosed breast cancer tend to have higher BMD than women with similar characteristics but without breast cancer. This implies that BMD might be considered a biomarker for breast cancer risk.
In recent years, several trials of breast cancer treatment have failed to demonstrate a survival benefit for some previously routine surgical therapies in selected patient groups. As each of these therapeutic approaches has been deemed of low value deimplementation has varied significantly. This demonstrates that effective de-escalation in breast cancer surgery relies on more than the availability of data from randomized controlled trials and other high-quality evidence, but is also influenced by various stakeholders, social expectations, and environmental contexts.
Background Rosai–Dorfman–Destombes disease (RDD) is a rare histiocytic disorder with heterogeneous clinical manifestations and rare neurologic involvement. The existing clinical literature about neurologic RDD has yet to be critically examined. Methods We performed a four-database English-language systematic literature search for cases of RDD neurohistiocytosis, excluding secondary literature. Individual patient data for neurologic symptoms, disease sites, treatments, and responses were captured. Responses to first-line and second-line surgical interventions, post-surgical radiotherapy, and systemic therapies were analyzed. Results Among 4769 articles yielded by literature search, 154 articles were fully reviewed, containing data on 224 patients with neurologic RDD. 128 (83.1%) articles were single case reports. 149 (66.5%) patients were male, 74 (33.5%) female, with a median age of 37.6 years (range 2–79). Presenting neurologic symptoms included headache (45.1%), focal neurological deficits (32.6%), visual symptoms (32.1%), and seizures (24.6%). RDD involvement was multifocal in 32 (14.3%) cases. First-line treatment involved resection in 200 (89.6%) patients, with subsequent progression in 52 (26%), including 41 (78.8%) with unifocal disease. No difference was observed in progression-free survival comparing post-operative radiotherapy to no radiotherapy following partial resection. Chemotherapy given alone as first-line treatment led to complete or partial response in 3/7(43%) patients. Second-line treatments led to complete or partial response in 18/37(37.5%) patients. Mutational data were reported on 10 patients (4.46%). Conclusions This review highlights the limited published data about neurologic RDD, which presents with varied symptomatology and outcome. Further study is needed about its mutational landscape, and more effective therapies are needed for recurrent and refractory disease.
Objectives While magnetic resonance imaging (MRI) is considered the gold standard for the imaging of female pelvis, there is an ongoing debate about the most appropriate indications and optimal imaging protocols. The European Society of Urogenital Radiology (ESUR) launched a survey to evaluate the current utilization of female pelvic MRI in clinical practice. Methods The ESUR female imaging subgroup developed an online survey that was then approved by the ESR board and circulated among the ESR members. The questions in the survey encompassed training and experience, indications for imaging and MR imaging protocols, reporting styles and preferences. The results of the survey were tabulated, and subgroups were compared using χ ² test. Results A total of 5900 ESR members with an interest in both MRI and female pelvic imaging were invited to participate; 840 (14.23%) members completed the survey. Approximately 50% of respondents were academic radiologists (50.6%) and nearly 60% women (59.69%). One third of the respondents were subspecialized in Gynecological imaging. Nearly half of the survey participants were aware of the presence of ESUR guidelines for imaging of the female pelvis (47.1%). The adoption of the ESUR recommendations was higher among subspecialized and/or academic and/or senior and/or European radiologists compared to all others. The current ESUR recommendations about female pelvic MRI protocols were generally followed. However wide variations in practice were identified with respect to the use of contrast media. Conclusion Female pelvic MRI protocol was generally following the ESUR recommendations, especially among subspecialized and academic radiologists. However, the fact that they are followed by only half of the participants highlights the need for wider awareness of these recommendations .
The Great Debate session at the 2021 Melanoma Bridge virtual congress (December 2–4) featured counterpoint views from experts on seven important issues in melanoma. The debates considered the use of adoptive cell therapy versus use of bispecific antibodies, mitogen-activated protein kinase (MAPK) inhibitors versus immunotherapy in the adjuvant setting, whether the use of corticosteroids for the management of side effects have an impact on outcomes, the choice of programmed death (PD)-1 combination therapy with cytotoxic T-lymphocyte-associated antigen (CTLA)-4 or lymphocyte-activation gene (LAG)-3, whether radiation is needed for brain metastases, when lymphadenectomy should be integrated into the treatment plan and then the last debate, telemedicine versus face-to-face. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. Audiences voted both before and after each debate.
International clinical practice guidelines have progressively endorsed direct oral anticoagulants (DOACs) as an alternative to low-molecular-weight heparins (LMWHs) monotherapy for the initial and long-term treatment of cancer-associated thrombosis (CAT). Several new randomized controlled trials (RCTs) have recently reported additional results on the safety and efficacy of DOACs in this setting. We performed an updated meta-analysis of all publicly available data from RCTs comparing DOACs with LMWHs for the treatment of CAT. Six RCTs enrolling 3690 patients with CAT were included. Compared with LMWHs, DOACs significantly decreased the risk of CAT recurrence (RR, 0.67; 95%CI, 0.52–0.85), with a non-significant increase in the risk of major bleeding (RR, 1.17; 95%CI, 0.82–1.67), a significant increase in the risk of clinically relevant nonmajor bleeding (RR 1.66; 95%CI, 1.31–2.09) and no difference in all-cause mortality rates. These results increase the level of certainty of available evidence supporting the use of DOACs as an effective and safe option for the treatment of CAT in selected cancer patients.
Over the past decade, immunotherapy has become an increasingly fundamental modality in the treatment of cancer. The positive impact of immune checkpoint inhibition, especially anti-programmed death (PD)-1/PD-ligand (L)1 blockade, in patients with different cancers has focused attention on the potential for other immunotherapeutic approaches. These include inhibitors of additional immune checkpoints, adoptive cell transfer (ACT), and therapeutic vaccines. Patients with advanced cancers who previously had limited treatment options available may now benefit from immunotherapies that can offer durable responses and improved survival outcomes. However, despite this, a significant proportion of patients fail to respond to immunotherapy, especially those with less immunoresponsive cancer types, and there remains a need for new treatment strategies. The virtual Immunotherapy Bridge (December 1st–2nd, 2021), organized by the Fondazione Melanoma Onlus, Naples, Italy in collaboration with the Society for Immunotherapy of Cancer addressed several areas of current research in immunotherapy, including lessons learned from cell therapies, drivers of immune response, and trends in immunotherapy across different cancers, and these are summarised here.
miR-486 is a muscle-enriched microRNA, or “myomiR,” that has reduced expression correlated with Duchenne muscular dystrophy (DMD). To determine the function of miR-486 in normal and dystrophin-deficient muscles and elucidate miR-486 target transcripts in skeletal muscle, we characterized mir-486 knockout mice ( mir-486 KO). mir-486 KO mice developed disrupted myofiber architecture, decreased myofiber size, decreased locomotor activity, increased cardiac fibrosis, and metabolic defects were exacerbated in mir-486 KO: mdx 5cv (DKO) mice. To identify direct in vivo miR-486 muscle target transcripts, we integrated RNA sequencing and chimeric miRNA eCLIP sequencing to identify key transcripts and pathways that contribute towards mir-486 KO and dystrophic disease pathologies. These targets included known and novel muscle metabolic and dystrophic structural remodeling factors of muscle and skeletal muscle contractile transcript targets. Together, our studies identify miR-486 as essential for normal muscle function, a driver of pathological remodeling in dystrophin-deficient muscle, a useful biomarker for dystrophic disease progression, and highlight the use of multiple omic platforms to identify in vivo microRNA target transcripts.
Background The benefit of chemotherapy for older patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (EBC) is a key area of debate. Gene expression profiling (GEP) may identify patients deriving benefit, but their predictive role has not been established for older adults. We summarise evidence on efficacy, safety, and quality-of-life impacts of chemotherapy and on GEP use and impact in older HR-positive, HER2-negative EBC patients. Methods We conducted a literature search of PubMed and Embase on publications describing prospective studies evaluating chemotherapy in older adults with HR-positive, HER2-negative EBC and on publications describing retrospective and prospective studies evaluating GEP in older adults. Results Eight publications on chemotherapy use, including 2,035 older patients with EBC were selected. Only one trial evaluated chemotherapy survival benefits in older adults, showing no benefit. Of four studies comparing different regimens, only one showed the superiority of taxanes versus anthracyclines alone. Those investigating alternative regimens did not show improvements over standard regimens despite significant limitations. Five publications on GEP, including 445,323 older patients, were included and investigated Oncotype DX. Limited evidence shows that GEP aids treatment decisions in this population. GEP was offered less frequently to older versus younger patients. Higher Recurrence Score was prognostic for distant recurrence, but chemotherapy did not improve prognosis. Conclusions In older patients with HR-positive, HER2-negative, chemotherapy survival benefits EBC are unclear and GEP is less used. Although its prognostic role is well established, its predictive role remains unknown.
Introduction It is unknown whether the ranking of plastic surgery residency programs influences resident research output. This study aims to determine whether program reputation and other factors are associated with integrated plastic surgery resident academic productivity. Materials and methods Programs were divided into four tiers based on Doximity reputation rankings. Residents from 2019 to 2020 were found through program websites and social media accounts. Works published during residency were identified through PubMed and Scopus from July 1 of each resident’s intern year to August 10, 2020. Variables included resident demographics and medical school, residency reputation ranking, geographic region, and medical school affiliation. ‘High research output’ was defined as having ≥75th percentile of publications adjusted by training year. Results In total, 921 residents in 80 programs were identified. The median (IQR) number of total publications and original articles was 3 (1-6) and 2 (0-4), respectively. On multivariable analysis, residents in top-20 ranked programs (OR = 2.31, 95% CI [1.55; 3.43], P < 0.001) or from programs associated with top-20 medical schools (OR = 1.61, 95% CI [1.08; 2.41], P = 0.020) were more likely to have higher research output. On the other hand, coming from a top-50 in research medical school (OR = 1.80, 95% CI [1.31; 2.47], P < 0.001) or being in a program affiliated with a top-20 medical school (OR = 2.52, 95% CI [1.69; 3.78], P < 0.001) were associated with higher original article output. Gender and geographic location were not associated with higher research output. Conclusions Program reputation and affiliated medical school research rankings are associated with research productivity during integrated plastic surgery residency. Applicants with a particular interest in research careers may consider this as they apply to residency.
Introduction Our study aims to highlight the role of Magnetic Resonance Imaging (MRI) in monitoring the therapeutic response after neoadjuvant chemotherapy in osteosarcoma of the long bones. Methods In this retrospective study, data from the Orthopaedics and Internal Medicine Department of Istanbul University Cerrahpasa Hospital was used. We selected the study cohort from our departmental database of patients with biopsy-proven osteosarcoma initially treated with preoperative chemotherapy at Istanbul University Cerrahpasa Hospital from 2010 to 2017. MRI images of 21 patients (male/female ratio: 2.5 with a mean age of 22) were analysed before and after neoadjuvant chemotherapy. The histological response to chemotherapy was graded according to The Huvos classification. Computed volumetry was performed to determine the size of the intramedullary component, largest enhancing component, and tumour volume. P < 0.05 was considered to denote a significant difference. Results The mean tumour volume before chemotherapy was 409 cm³. After chemotherapy, however, the tumor volume increased to 701 cm³ (p = 0.10). The mean intramedullary component size of the tumours before chemotherapy was 10.5 cm³ while after chemotherapy was 11.2 cm³ (p = 0.06). The mean largest enhancing component size was 3.09 cm³ and after chemotherapy, decreased to 2.34 cm³ (p = 0.01). Neoadjuvant chemotherapy significantly changed the tumour composition. Tumour volume and intramedullary component size measurements failed to demonstrate a significant correlation and could not be used as a prognostic factor for tumour response to preoperative chemotherapy. We suggest that the largest enhancing component of a tumour can be a potential prognostic marker for assessing the tumour response. Conclusion MRI can help predict histological necrosis after the administration of preoperative chemotherapy to osteosarcoma via measuring the largest enhancing component. Hence, it is a promising preoperative indicator of response to neoadjuvant chemotherapy. However, tumour volume and intramedullary component size measurement are not effective predictors of histological necrosis. The increased volume and intramedullary component of the tumour were attributed to the increased central necrotic component of the tumour after chemotherapy. Implications for practice In this study, we showed that MRI can help predict histological necrosis and thus, prognosis after the administration of preoperative chemotherapy to osteosarcoma via the measurement of the largest enhancing component of the tumour. This is significant because histological necrosis is currently the gold standard method for assessing the treatment response. However, this requires an invasive procedure, and a non-invasive method would be beneficial. Assessing the treatment response through imaging after the completion of the initial chemotherapy will also help determine the final surgical approach and thus predict survival.
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