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1.
Dev Biol ; 511: 12-25, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38556137

ABSTRACT

During epithelial morphogenesis, the apical junctions connecting cells must remodel as cells change shape and make new connections with their neighbors. In the C. elegans embryo, new apical junctions form when epidermal cells migrate and seal with one another to encase the embryo in skin ('ventral enclosure'), and junctions remodel when epidermal cells change shape to squeeze the embryo into a worm shape ('elongation'). The junctional cadherin-catenin complex (CCC), which links epithelial cells to each other and to cortical actomyosin, is essential for C. elegans epidermal morphogenesis. RNAi genetic enhancement screens have identified several genes encoding proteins that interact with the CCC to promote epidermal morphogenesis, including the scaffolding protein Afadin (AFD-1), whose depletion alone results in only minor morphogenesis defects. Here, by creating a null mutation in afd-1, we show that afd-1 provides a significant contribution to ventral enclosure and elongation on its own. Unexpectedly, we find that afd-1 mutant phenotypes are strongly modified by diet, revealing a previously unappreciated parental nutritional input to morphogenesis. We identify functional interactions between AFD-1 and the CCC by demonstrating that E-cadherin is required for the polarized distribution of AFD-1 to cell contact sites in early embryos. Finally, we show that afd-1 promotes the enrichment of polarity regulator, and CCC-interacting protein, PAC-1/ARHGAP21 to cell contact sites, and we identify genetic interactions suggesting that afd-1 and pac-1 regulate epidermal morphogenesis at least in part through parallel mechanisms. Our findings reveal that C. elegans AFD-1 makes a significant contribution to epidermal morphogenesis and functionally interfaces with core and associated CCC proteins.


Subject(s)
Cadherins , Caenorhabditis elegans Proteins , Caenorhabditis elegans , Epidermis , Morphogenesis , Animals , Cadherins/metabolism , Cadherins/genetics , Caenorhabditis elegans/embryology , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Catenins/metabolism , Catenins/genetics , Epidermal Cells/metabolism , Epidermis/metabolism , Epidermis/embryology , GTPase-Activating Proteins/metabolism , GTPase-Activating Proteins/genetics , Microfilament Proteins/metabolism , Microfilament Proteins/genetics
2.
Article in English | MEDLINE | ID: mdl-38796676

ABSTRACT

This randomized controlled trial tested the Family Assessment and Feedback Intervention (FAFI), a new intervention to enhance family engagement with emotional and behavioral health services. The FAFI is a guided conversation with families about results of their multidimensional assessment that is set in the context of motivational enhancement. It differs from other assessment-with-feedback interventions by extending the focus of assessment beyond the target child to parents and the family environment, addressing parental emotional and behavioral problems and competencies, spanning a broad range of children's and parents' strengths and difficulties, and being generalizable to many settings and practitioners. Participants were 81 families in primary care pediatrics. The FAFI was associated with a significant increase in parental mental health literacy and with an increase in parental attitudinal engagement with health supports and services that closely approached statistical significance (p = .052), while controlling for children's age and gender and family socioeconomic status.

3.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: mdl-34117742

ABSTRACT

Most tissue collections of neoplasms are composed of formalin-fixed and paraffin-embedded (FFPE) excised tumor samples used for routine diagnostics. DNA sequencing is becoming increasingly important in cancer research and clinical management; however it is difficult to accurately sequence DNA from FFPE samples. We developed and validated a new bioinformatic pipeline to use existing variant-calling strategies to robustly identify somatic single nucleotide variants (SNVs) from whole exome sequencing using small amounts of DNA extracted from archival FFPE samples of breast cancers. We optimized this strategy using 28 pairs of technical replicates. After optimization, the mean similarity between replicates increased 5-fold, reaching 88% (range 0-100%), with a mean of 21.4 SNVs (range 1-68) per sample, representing a markedly superior performance to existing tools. We found that the SNV-identification accuracy declined when there was less than 40 ng of DNA available and that insertion-deletion variant calls are less reliable than single base substitutions. As the first application of the new algorithm, we compared samples of ductal carcinoma in situ of the breast to their adjacent invasive ductal carcinoma samples. We observed an increased number of mutations (paired-samples sign test, P < 0.05), and a higher genetic divergence in the invasive samples (paired-samples sign test, P < 0.01). Our method provides a significant improvement in detecting SNVs in FFPE samples over previous approaches.


Subject(s)
Biomarkers, Tumor , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Computational Biology/methods , Polymorphism, Single Nucleotide , DNA, Neoplasm , Female , Genetic Heterogeneity , Genetic Testing/methods , Genetic Testing/standards , High-Throughput Nucleotide Sequencing , Humans , Mutation , Workflow
4.
World J Surg ; 47(2): 545-551, 2023 02.
Article in English | MEDLINE | ID: mdl-36329222

ABSTRACT

BACKGROUND: Gastroschisis mortality in sub-Saharan Africa (SSA) remains high at 59-100%. Silo inaccessibility contributes to this disparity. Standard of care (SOC) silos cost $240, while median monthly incomes in SSA are < $200. Our multidisciplinary American and Ugandan team designed and bench-tested a low-cost (LC) silo that costs < $2 and is constructed from locally available materials. Here we describe in vivo LC silo testing. METHODS: A piglet gastroschisis model was achieved by eviscerating intestines through a midline incision. Eight piglets were randomized to LC or SOC silos. Bowel was placed into the LC or SOC silo, maintained for 1-h, and reduced. Procedure times for placement, intestinal reduction, and silo removal were recorded. Tissue injury of the abdominal wall and intestine was assessed. Bacterial and fungal growth on silos was also compared. RESULTS: There were no gross injuries to abdominal wall or intestine in either group or difference in minor bleeding. Times for silo application, bowel reduction, and silo removal between groups were not statistically or clinically different, indicating similar ease of use. Microbiologic analysis revealed growth on all samples, but density was below the standard peritoneal inoculum of 105 CFU/g for both silos. There was no significant difference in bacterial or fungal growth between LC and SOC silos. CONCLUSION: LC silos designed for manufacturing and clinical use in SSA demonstrated similar ease of use, absence of tissue injury, and acceptable microbiology profile, similar to SOC silos. The findings will allow our team to proceed with a pilot study in Uganda.


Subject(s)
Abdominal Wall , Gastroschisis , Plastic Surgery Procedures , Animals , Abdominal Wall/surgery , Gastroschisis/surgery , Intestines/surgery , Pilot Projects , Swine
5.
Child Psychiatry Hum Dev ; 54(5): 1297-1308, 2023 10.
Article in English | MEDLINE | ID: mdl-35246775

ABSTRACT

This randomized controlled trial tested the Vermont Family Based Approach (VFBA) in primary care pediatrics. The VFBA is a model of healthcare delivery that shifts the focus from the individual to the family, emphasizes emotional and behavioral health, and uses evidence-based health promotion/prevention along with the treatment of emotional and behavioral problems. Participants were 81 families of 3-15-year-olds. For children, the VFBA was associated with greater reductions than the Control condition on the Child Behavior Checklist Emotionally Reactive, Withdrawn, Sleep Problems, Aggressive Behavior and Total Problems scales. For parents, the VFBA was associated with greater reductions than the Control condition on the Adult Self-Report Anxious/Depressed, Rule-Breaking Behavior, Internalizing Problems and Total Problems scales. The VFBA was also associated with greater improvement than the Control condition in the parents' health-related quality of life, as indicated by all scales of the Medical Outcomes Study Health Survey.


Subject(s)
Problem Behavior , Adult , Child , Humans , Vermont , Quality of Life , Parents/psychology , Primary Health Care
6.
Radiology ; 302(2): 246-255, 2022 02.
Article in English | MEDLINE | ID: mdl-34931856

ABSTRACT

Ductal carcinoma in situ (DCIS) is a nonobligate precursor of invasive cancer, and its detection, diagnosis, and management are controversial. DCIS incidence grew with the expansion of screening mammography programs in the 1980s and 1990s, and DCIS is viewed as a major driver of overdiagnosis and overtreatment. For pathologists, the diagnosis and classification of DCIS is challenging due to undersampling and interobserver variability. Understanding the progression from normal breast tissue to DCIS and, ultimately, to invasive cancer is limited by a paucity of natural history data with multiple proposed evolutionary models of DCIS initiation and progression. Although radiologists are familiar with the classic presentation of DCIS as asymptomatic calcifications at mammography, the expanded pool of modalities, advanced imaging techniques, and image analytics have identified multiple potential biomarkers of histopathologic characteristics and prognosis. Finally, there is growing interest in the nonsurgical management of DCIS, including active surveillance, to reduce overtreatment and provide patients with more personalized management options. However, current biomarkers are not adept at enabling identification of occult invasive disease at biopsy or accurately predicting the risk of progression to invasive disease. Several active surveillance trials are ongoing and are expected to better identify women with low-risk DCIS who may avoid surgery.


Subject(s)
Breast Neoplasms/diagnostic imaging , Carcinoma in Situ/diagnostic imaging , Carcinoma, Ductal, Breast/diagnostic imaging , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Carcinoma in Situ/pathology , Carcinoma in Situ/therapy , Carcinoma, Ductal, Breast/pathology , Carcinoma, Ductal, Breast/therapy , Early Detection of Cancer , Female , Humans , Prognosis
7.
Catheter Cardiovasc Interv ; 99(6): 1733-1740, 2022 05.
Article in English | MEDLINE | ID: mdl-35349771

ABSTRACT

OBJECTIVES: To investigate the perceptions of interventional cardiologists (IC) regarding the frequency, impact, and management strategies of percutaneous coronary intervention (PCI) complications. BACKGROUND: The perceptions and management strategies of ICs of PCI complications have received limited study. METHODS: Online survey on PCI complications: 46 questions were distributed via email lists and Twitter to ICs. RESULTS: Of 11,663 contacts, 821 responded (7% response rate): 60% were from the United States and the median age was 46-50 years. Annual PCI case numbers were <100 (26%), 100-199 (37%), 200-299 (21%), and ≥300 (16%); 42% do not perform structural interventions, others reported performing <40 (30%), or >100 (11%) structural cases annually. On a scale of 0-10, participating ICs were highly concerned about potential complications with a median score of 7.2 (interquartile range: 5.0-8.7). The most feared complication was death (39%), followed by coronary perforation (26%) and stroke (9%). Covered stents were never deployed by 21%, and 32% deployed at least one during the past year; 79% have never used fat to seal perforations; 64% have never used coils for perforations. Complications were attributed to higher patient/angiographic complexity by 68% and seen as opportunities for improvement by 70%; 97% of participants were interested in learning more about the management of PCI complications. The most useful learning methods were meetings (66%), webinars (48%), YouTube (32%), and Twitter (29%). CONCLUSION: ICs who participated in the survey are highly concerned about complications. Following complication management algorithms and having access to more experienced operators might alleviate stress and optimize patient outcomes.


Subject(s)
Cardiologists , Heart Injuries , Percutaneous Coronary Intervention , Humans , Middle Aged , Percutaneous Coronary Intervention/adverse effects , Surveys and Questionnaires , Treatment Outcome , United States/epidemiology
8.
Am J Bot ; 109(11): 1875-1892, 2022 11.
Article in English | MEDLINE | ID: mdl-36063430

ABSTRACT

PREMISE: In the absence of hawkmoth pollinators, chasmogamous (CH) flowers of Ruellia humilis self-pollinate by two secondary mechanisms. Other floral visitors might exert selection on CH floral traits to restore outcrossing, but at the same time preferential predation of CH seeds generates selection to increase the allocation of resources to cleistogamous (CL) flowers. METHODS: To assess the potential for an evolutionary response to these competing selection pressures, we estimated additive genetic variances ( σ A 2 ${\sigma }_{{\rm{A}}}^{2}$ ) and covariances for 14 reproductive traits and three fitness components in a Missouri population lacking hawkmoth pollinators. RESULTS: We found significant σ A 2 ${\sigma }_{{\rm{A}}}^{2}$ for all 11 floral traits and two measures of resource allocation to CL flowers, indicating the potential for a short-term response to selection on most reproductive traits. Selection generated by seed predators is predicted to increase the percentage of CL flowers by 0.24% per generation, and mean stigma-anther separation is predicted to decrease as a correlated response, increasing the fraction of plants that engage in prior selfing. However, the initial response to this selection is opposed by strong directional dominance. CONCLUSIONS: The predicted evolutionary decrease in the number of CH flowers available for potential outcrossing, combined with the apparent preclusion of potential diurnal pollinators by the pollen-harvesting activities of sweat bees, suggest that 100% cleistogamy is the likely outcome of evolution in the absence of hawkmoths. However, rare mutations with large effects, such as delaying budbreak until after sunrise, could provide pathways for the restoration of outcrossing that are not reachable by gradual quantitative-genetic evolution.


Subject(s)
Acanthaceae , Manduca , Bees , Animals , Pollination/physiology , Flowers/genetics , Pollen/genetics , Acanthaceae/physiology , Reproduction
9.
Breast J ; 2022: 7146172, 2022.
Article in English | MEDLINE | ID: mdl-35833190

ABSTRACT

Background: Randomized studies of neoadjuvant (NA) trastuzumab and pertuzumab combined with chemotherapy for HER2-positive breast cancers (BC) have reported pathological complete response (pCR) rates of 39 to 61%. This study aimed to determine the real-world efficacy and toxicity of NA trastuzumab and pertuzumab combined with chemotherapy in a UK tertiary referral cancer centre. Methods: HER2-positive early BC patients given neoadjuvant chemotherapy with trastuzumab and pertuzumab between October 2016 and February 2018 at our tertiary referral cancer centre were identified via pharmacy records. Clinico-pathological information, treatment regimens, treatment-emergent toxicities, operative details, and pathological responses and outcomes were recorded. Results: 78 female patients were identified; 2 had bilateral diseases and 48 of 78 (62%) were node positive at presentation. 55 of 80 (71%) tumours were ER-positive. PCR occurred in 37 of 78 (46.3%; 95% CI: 35.3-57.2%) patients. 14 of 23 (60.8%) patients with ER-negative tumours achieved pCR; 23 of 55 (41.8%) were ER-positive and 6 of 19 (31.6%) were ER-positive and PgR-positive. No cardiac toxicity was documented. Diarrhoea occurred in 53 of 72 (74%) patients. Grade 3-4 toxicity occurred in ≥2% patients. These were diarrhoea, fatigue, and infection. The Median follow up period was 45.2 months (95% CI 43.8-46.3) with 71 of 78 (91.0%) remaining disease-free and 72 of 78 (92.3%) alive. Estimated OS at 2 years 86% (95% CI: 75-99%). Conclusion: This data confirms the efficacy of neoadjuvant chemotherapy combined with dual HER2 directed therapy. While no cardiac toxicity was observed, diarrhoea occurred frequently. The low pCR rate observed in ER and PgR-positive BCs warrants further investigation and consideration of strategies to increase the pCR rate.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms , Neoadjuvant Therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/toxicity , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Diarrhea/chemically induced , Diarrhea/epidemiology , Female , Humans , Neoadjuvant Therapy/adverse effects , Trastuzumab/therapeutic use , Treatment Outcome
10.
BMC Cancer ; 21(1): 1051, 2021 Sep 25.
Article in English | MEDLINE | ID: mdl-34563146

ABSTRACT

BACKGROUND: The association between obesity and breast cancer (BC) has been extensively studied among US, European and Asian study populations, with often conflicting evidence. However, despite the increasing prevalence of obesity and associated conditions in Africa, the continent with the highest age-standardized BC mortality rate globally, few studies have evaluated this association, and none has examined in relation to molecular subtypes among African women. The current analysis examines the association between body composition, defined by body mass index (BMI), height, and weight, and BC by molecular subtype among African women. METHODS: We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) for the association between measures of body composition and BC and molecular subtypes among 419 histologically confirmed cases of BC and 286 healthy controls from the Mechanisms for Established and Novel Risk Factors for Breast Cancer in Women of Nigerian Descent (MEND) case-control study. RESULTS: Higher BMI (aOR: 0.79; 95% CI: 0.67, 0.95) and weight (aOR: 0.83; 95% CI: 0.69, 0.98) were associated with reduced odds of BC in adjusted models, while height was associated with non-statistically significant increased odds of BC (aOR: 1.07, 95% CI: 0.90, 1.28). In pre/peri-menopausal, but not post-menopausal women, both higher BMI and weight were significantly associated with reduced odds of BC. Further, higher BMI was associated with reduced odds of Luminal A, Luminal B, and HER2-enriched BC among pre/peri-menopausal women, and reduced odds of triple-negative BC among post-menopausal women. CONCLUSIONS: Higher BMI and weight were associated with reduced odds of BC overall and by molecular subtype among West African women. Larger studies of women of African descent are needed to definitively characterize these associations and inform cancer prevention strategies.


Subject(s)
Body Composition , Breast Neoplasms/etiology , Adult , Body Height , Body Mass Index , Body Weight , Breast Neoplasms/chemistry , Case-Control Studies , Confidence Intervals , Female , Humans , Menopause , Middle Aged , Nigeria , Odds Ratio , Reproductive History , Risk Factors , Triple Negative Breast Neoplasms/chemistry , Triple Negative Breast Neoplasms/etiology
11.
Int J Gynecol Pathol ; 40(6): 587-596, 2021 Nov 01.
Article in English | MEDLINE | ID: mdl-33720082

ABSTRACT

The study evaluated morphologic patterns, mutational profiles, and ß-catenin immunohistochemistry (IHC) in copy-number low (CNL) endometrial adenocarcinomas (EAs). CNL EAs (n=19) with next-generation or whole genome sequencing results and available tissue for IHC were identified from our institutional database. Clinical data and histologic slides were reviewed. IHC for ß-catenin was performed and correlated with mutation status. Images of digital slides of CNL EAs from The Cancer Genome Atlas (TCGA) database (n=90) were blindly reviewed by 4 pathologists, and morphology was correlated with mutation status. Categorical variables were analyzed using the Fisher exact test, and agreement was assessed using Fleiss κ. CTNNB1 mutations were present in 63% (12/19) of CNL EAs. ß-catenin nuclear localization was present in 83% of CTNNB1-mutated tumors (10/12) and in 0% (0/7) of CTNNB1-wildtype tumors (sensitivity 0.83, specificity 1.00). Squamous differentiation (SD) was present in 47% (9/19) and was more often observed in CTNNB1-mutated tumors (P=0.02). Mucinous differentiation (MD) was associated with KRAS mutations (P<0.01). Digital image review of TCGA CNL EAs revealed that pathologist agreement on SD was strong (κ=0.82), whereas agreement on MD was weak (κ=0.48). Pathologists identified SD in 22% (20/90), which was significantly associated with the presence of CTNNB1 mutations (P<0.01). CNL EAs demonstrate several morphologies with divergent molecular profiles. SD was significantly associated with CTNNB1 mutations and nuclear localization of ß-catenin in these tumors. Nuclear expression of ß-catenin is a sensitive and specific IHC marker for CTNNB1 mutations in CNL EAs. CNL EAs with KRAS mutations often displayed MD.


Subject(s)
Adenocarcinoma , Endometrial Neoplasms , Adenocarcinoma/diagnosis , Adenocarcinoma/genetics , DNA Mutational Analysis , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/genetics , Female , Humans , Immunohistochemistry , Mutation , beta Catenin/genetics
12.
Catheter Cardiovasc Interv ; 96(5): 1029-1035, 2020 11.
Article in English | MEDLINE | ID: mdl-31797507

ABSTRACT

BACKGROUND: When crossing into the distal true lumen fails during chronic total occlusion (CTO) percutaneous coronary intervention (PCI), subintimal plaque modification (SPM) is often performed to restore antegrade flow and facilitate subsequent lesion recanalization. METHODS: Between January 2012 and May 4, 2019, 4,659 CTO PCIs were included in the PROGRESS-CTO registry, of which 935 (20%) had a prior unsuccessful attempt. Of those 935 patients, 119 (13%) had prior SPM. We analyzed the outcomes of the 58 SPM procedures for which data were available, as well as the outcomes of the 60 subsequent CTO PCI attempts. RESULTS: Mean patient age was 67 ± 9 years and 86% were men. Patients had high prevalence of cardiovascular risk factors such as dyslipidemia (91%), hypertension (93%) diabetes (48%), prior PCI (61%), and prior coronary artery bypass graft surgery (47%). The target CTO lesions often had proximal cap ambiguity (54%), moderate/severe calcification (73%), moderate/severe tortuosity (63%), and high J-CTO score (mean 3.2 ± 1.1). The technical and procedural success of subsequent CTO PCI were high (83% for both) with an acceptable rate of in-hospital major adverse cardiovascular events (3.3%). Technical and procedural success were higher for repeat attempts that were performed ≥60 days after the index CTO PCI (94% vs. 69%, p = .015). Median (interquartile range) subsequent procedure time was 147 (100, 215) min, contrast volume was 185 (150, 260) ml, and air kerma radiation dose was 2.5 (1.4, 4.2) Gray. CONCLUSION: Repeat CTO PCI attempts after SPM are associated with high likelihood for successful revascularization with acceptable risks.


Subject(s)
Coronary Artery Disease/therapy , Coronary Occlusion/therapy , Percutaneous Coronary Intervention , Plaque, Atherosclerotic , Aged , Chronic Disease , Coronary Artery Disease/diagnostic imaging , Coronary Occlusion/diagnostic imaging , Female , Humans , Male , Middle Aged , Percutaneous Coronary Intervention/adverse effects , Registries , Retrospective Studies , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome
13.
Catheter Cardiovasc Interv ; 93(2): 199-201, 2019 02 01.
Article in English | MEDLINE | ID: mdl-30719852

ABSTRACT

The Subintimal Tracking and Reentry (STAR) technique is not suitable for routine use during chronic total occlusion percutaneous coronary intervention due to side branch loss and long stent length, leading to high restenosis and re-occlusion rates. STAR without stenting (also called subintimal plaque modification [SPM]) can be used as a bailout strategy in CTO PCI, when standard crossing attempts fail. Repeat angiography is performed 2-4 months later, often showing lumen reconstitution and dissection healing, at which time the intervention can be successfully completed in many cases. Subintimal plaque modification may become an important element of the expanded hybrid algorithm. Four parameters are constantly being evaluated during the procedure: radiation dose, contrast volume, procedure time and risk of the remaining treatment options, to determine if the procedure needs to stop. Before stopping, SPM may be used to facilitate future success.


Subject(s)
Coronary Occlusion , Percutaneous Coronary Intervention , Chronic Disease , Coronary Angiography , Humans , Referral and Consultation , Stents , Treatment Outcome
14.
Catheter Cardiovasc Interv ; 93(3): E193-E194, 2019 02 15.
Article in English | MEDLINE | ID: mdl-30770658

ABSTRACT

Saphenous vein graft (SVG) percutaneous coronary intervention carries high rates of acute (no reflow and periprocedural myocardial infarction) and long-term (restenosis and re-occlusion) complications. Long-term follow-up from the two largest trials of drug-eluting vs. bare metal stents in SVG lesions (The Drug-Eluting Stents vs. Bare Metal Stents In Saphenous Vein graft Angioplasty and Is Drug-Eluting-Stenting Associated with Improved Results in Coronary Artery Bypass Grafts? Trial) definitely show no difference between the two stent types, suggesting that bare metal stents should be preferred given lower cost. Since SVG stenting remains associated with high failure rates, alternative treatment strategies, such as intervention of the corresponding native coronary artery lesions, may represent the future direction of the field.


Subject(s)
Drug-Eluting Stents , Transplants , Graft Occlusion, Vascular , Humans , Metals , Prosthesis Design , Randomized Controlled Trials as Topic , Saphenous Vein , Stents , Treatment Outcome
15.
J Natl Compr Canc Netw ; 17(2): 171-189, 2019 02.
Article in English | MEDLINE | ID: mdl-30787130

ABSTRACT

As treatment of HIV has improved, people living with HIV (PLWH) have experienced a decreased risk of AIDS and AIDS-defining cancers (non-Hodgkin's lymphoma, Kaposi sarcoma, and cervical cancer), but the risk of Kaposi sarcoma in PLWH is still elevated about 500-fold compared with the general population in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AIDS-Related Kaposi Sarcoma provide diagnosis, treatment, and surveillance recommendations for PLWH who develop limited cutaneous Kaposi sarcoma and for those with advanced cutaneous, oral, visceral, or nodal disease.


Subject(s)
AIDS-Related Opportunistic Infections/diagnosis , AIDS-Related Opportunistic Infections/therapy , Sarcoma, Kaposi/diagnosis , Sarcoma, Kaposi/therapy , AIDS-Related Opportunistic Infections/epidemiology , AIDS-Related Opportunistic Infections/etiology , Humans , Sarcoma, Kaposi/epidemiology , Sarcoma, Kaposi/etiology
16.
Pediatr Cardiol ; 40(7): 1388-1400, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31372681

ABSTRACT

In this article, we provide a brief summary of work by us and others to discover the molecular underpinnings of early conduction system development and function. We focus on how the multifunctional protein Tbx3 contributes to acquisition and homeostasis of the tissue-specific properties of the sinoatrial and atrioventricular nodes. We also provide unpublished, preliminary findings supporting the role of Tbx3-regulated alternative RNA processing in the developing conduction system.


Subject(s)
Gene Expression Regulation, Developmental , Heart Conduction System/metabolism , Animals , Atrioventricular Node/physiopathology , Gene Expression , Heart Conduction System/embryology , Humans , RNA/metabolism , T-Box Domain Proteins
17.
Breast Cancer Res Treat ; 172(1): 123-132, 2018 Nov.
Article in English | MEDLINE | ID: mdl-29992418

ABSTRACT

PURPOSE: The purpose of the study was to define quantitative measures of intra-tumor heterogeneity in breast cancer based on histopathology data gathered from multiple samples on individual patients and determine their association with distant recurrence-free survival (DRFS). METHODS: We collected data from 971 invasive breast cancers, from 1st January 2000 to 23rd March 2014, that underwent repeat tumor sampling at our institution. We defined and calculated 31 measures of intra-tumor heterogeneity including ER, PR, and HER2 immunohistochemistry (IHC), proliferation, EGFR IHC, grade, and histology. For each heterogeneity measure, Cox proportional hazards models were used to determine whether patients with heterogeneous disease had different distant recurrence-free survival (DRFS) than those with homogeneous disease. RESULTS: The presence of heterogeneity in ER percentage staining was prognostic of reduced DRFS with a hazard ratio of 4.26 (95% CI 2.22-8.18, p < 0.00002). It remained significant after controlling for the ER status itself (p < 0.00062) and for patients that had chemotherapy (p < 0.00032). Most of the heterogeneity measures did not show any association with DRFS despite the considerable sample size. CONCLUSIONS: Intra-tumor heterogeneity of ER receptor status may be a predictor of patient DRFS. Histopathologic data from multiple tissue samples may offer a view of tumor heterogeneity and assess recurrence risk.


Subject(s)
Biomarkers, Tumor , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Disease-Free Survival , Female , Humans , Immunohistochemistry , Middle Aged , Neoplasm Grading , Neoplasm Recurrence, Local , Neoplasm Staging , Prognosis , Proportional Hazards Models , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Retrospective Studies , Tumor Burden , Young Adult
18.
Ann Surg Oncol ; 25(8): 2249-2260, 2018 Aug.
Article in English | MEDLINE | ID: mdl-29855830

ABSTRACT

BACKGROUND: Metaplastic breast cancer (MBC) is characterized by chemoresistance and hematogenous spread. We sought to identify factors associated with improved MBC outcomes and increased likelihood of MBC diagnosis. METHODS: Women ≥ 18 years of age with stage I-III MBC and non-MBC diagnosed between 2010 and 2014 were identified in the National Cancer Data Base. Kaplan-Meier and multivariate Cox proportional hazards models were used to estimate associations with overall survival (OS). Multivariate logistic regression identified factors associated with MBC diagnosis. RESULTS: Overall, 2451 MBC and 568,057 non-MBC patients were included; 70.3% of MBC vs. 11.3% of non-MBC patients were triple negative (p < 0.001). Five-year OS was reduced among MBC vs. non-MBC patients for the entire cohort (72.7 vs. 87.5%) and among triple-negative patients (71.1 vs. 77.8%; both p < 0.001). In MBC, triple-negative (vs. luminal) subtype was not associated with worse OS (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.88-1.54, p = 0.28). Compared with non-MBC patients, MBC patients were more likely to receive mastectomy (59.0 vs. 44.9%), chemotherapy (74.1 vs. 43.1%), and axillary lymph node dissection (ALND; 35.2 vs. 32.2%, all p ≤ 0.001). MBC patients more frequently had negative ALND (pN0) than non-MBC patients (20.0 vs. 10.6%, p < 0.001). Among MBC patients, chemotherapy (HR 0.69, 95% CI 0.53-0.89, p = 0.004) and radiotherapy (HR 0.52, 95% CI 0.39-0.69, p < 0.001) were associated with improved survival, while ALND was associated with decreased survival (HR 1.37, 95% CI 1.06-1.77, p = 0.02). CONCLUSIONS: MBC patients had worse survival than non-MBC patients, independent of receptor status, suggesting that MBC may confer an additional survival disadvantage. Multimodal therapy was associated with improved outcomes, but ALND was not and may be overutilized in MBC.


Subject(s)
Breast Neoplasms/therapy , Databases, Factual , Metaplasia/therapy , Aged , Axilla , Breast Neoplasms/pathology , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Metaplasia/pathology , Middle Aged , Prognosis , Retrospective Studies , Survival Rate
19.
Int J Gynecol Pathol ; 37(3): 252-255, 2018 May.
Article in English | MEDLINE | ID: mdl-28700428

ABSTRACT

To determine whether the processing of additional adipose tissue collected during lymph node (LN) dissection results in the identification of additional LNs during endometrial cancer (EC) staging and to determine if the division of LNs into nodal basin-specific specimens has an effect on the number of LNs identified during EC staging. A prospective randomized controlled trial was performed on women with high-grade EC undergoing surgical staging. Subjects were randomized to collection of LNs into nodal basin-specific containers on the randomized side versus simple labeling on the nonrandomized side. The total number of LNs and total number of LNs with metastases on the randomized versus the nonrandomized side were compared. The remaining adipose tissue from each LN specimen was submitted for histologic examination. We analyzed the number of LNs with and without metastases identified from additional adipose tissue. Of 120 consented subjects, 56 had sufficient data for analysis. The additional adipose tissue contained 7.5 additional LNs per patient on average (range: 0-26). In 2/54 total cases (3.7%) and 2/5 cases with nodal metastases (40%), the additional adipose contained LNs with metastases. In both cases, metastases were also detected in grossly identified LN candidates. The mean number of LNs identified was not significantly different based on method of collection (P=0.22). The mean number of LNs containing metastases per side was not significantly different (P=0.58). Processing of adipose tissue does increase the total number of LNs identified, however, it does not influence EC stage. No difference in LN counts was noted with basin-specific collection.


Subject(s)
Endometrial Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Biopsy , Female , Humans , Lymph Node Excision , Lymph Nodes/pathology , Lymphatic Metastasis/pathology , Middle Aged , Neoplasm Staging , Prospective Studies
20.
Int J Eat Disord ; 51(5): 475-479, 2018 05.
Article in English | MEDLINE | ID: mdl-29740834

ABSTRACT

Gender nonconforming youth are at risk for body dissatisfaction and disordered eating. Currently, only a small body of literature addresses this high-risk group. The five cases in this series highlight important themes for this patient population from an interdisciplinary perspective. Identified themes include increased risk for self-harm/suicide, complex psychiatric, and medical implications of delay to treatment for either gender dysphoria or disordered eating, and the importance of collaborative management to maximize care and facilitate healthy development to adulthood. The purpose of this case series is to expand the interdisciplinary discussion regarding the breadth of presentation and management considerations for gender nonconforming adolescents with disordered eating. An interdisciplinary approach to care might enhance access to comprehensive, collaborative treatment for disordered eating, and gender dysphoria in this unique population.


Subject(s)
Feeding and Eating Disorders/psychology , Gender Dysphoria/psychology , Transgender Persons/psychology , Adolescent , Female , Humans , Male , Retrospective Studies
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