tbuckley/cabot-search huggingface dataset:
AB0215 Multicentric reticulohistiocytosis: a case report
Authors: F Göðüþ, G Kaymak Karataþ, M Beyazova, V Sepici
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Multicentric reticulohistiocytosis is a rare systemic illness which primarily affects joints and skin. The illness has a female predominance and usually begins during the fourth decade.<sup>1</sup> <h3>Objectives</h3> We describe a patient with multicentric reticulohistiocytosis whose manifestations have started at a much younger age than mentioned in the literature. <h3>Methods</h3> <h3>Results</h3> 18-year-old female patient presented with a complaint of arthralgia at her wrists, knees and ankles. Her complaints had started 6 months before admission with arthralgia and painful swellings at the wrists and kness. On admission she had active symmetric arthritis at the shoulders, elbows, wrists and knees. Synovial hypertrophy was prominent at the wrists, knees and MCP joints. Cutaneous examination showed a single 0.5 × 0.5 cm erythematous nodular structure at her 3 MCP joint. There were orange coloured hypertrophic lesions at her nail-folds. Her systemic examination was not remarkable. Her ESR was 29 mm/h, CRP 96 mg/dl, RF(-), Hb: 11.5, WBC: 10.300, platelets 289.000. Liver and kidney functions were normal. x-rays of the hands showed periarticular osteopenia, there were no erosions. Arthrosyntesis showed the characteristics of an inflammatory synovial fluid. She was thought to have active rheumatoid arthritis and was started on 7.5 mg prednisolone and sulphasalazine 2 g/day. The dosage of prednisolone was gradually increased to 30 mg/day as there was no improvement in her active arthritis. Methotrexate 7.5 mg/week was added. During her follow-up she developed orange papulonodular lesions on her forehead and pinnae. Biopsy taken from the 3MCP joint revealed reticulohistiocytoma. 10 months after the diagnosis she is still under close surveillence as the disease can be associated with malignancy in 25% of patients. She is currently on methotrexate 12.5 mg/week and prednisolone 20 mg/day. The active arthritis at the shoulders and knees has resolved but she still has active arthritis at the wrists. <h3>Conclusion</h3> Although multicentric reticulohistiocytosis affects predominantly middle-aged women the disease should be kept in mind in the differential diagnosis of active arthritis for younger age groups as well. <h3>Reference</h3> Yee KC, <i>et al</i>. Clin Exp Rheumatol. 1993;18: 555–8
Maintenance of Adaptive Dynamics and No Detectable Load in a Range-Edge Outcrossing Plant Population
Authors: Margarita Takou, Tuomas Hämälä, Evan M Koch, Kim A Steige, Hannes Dittberner, Levi Yant, Mathieu Genete, Shamil Sunyaev, Vincent Castric, Xavier Vekemans, Outi Savolainen, Juliette de Meaux
Journal: Molecular Biology and Evolution (2021)

During range expansion, edge populations are expected to face increased genetic drift, which in turn can alter and potentially compromise adaptive dynamics, preventing the removal of deleterious mutations and slowing down adaptation. Here, we contrast populations of the European subspecies Arabidopsis lyrata ssp. petraea, which expanded its Northern range after the last glaciation. We document a sharp decline in effective population size in the range-edge population and observe that nonsynonymous variants segregate at higher frequencies. We detect a 4.9% excess of derived nonsynonymous variants per individual in the range-edge population, suggesting an increase of the genomic burden of deleterious mutations. Inference of the fitness effects of mutations and modeling of allele frequencies under the explicit demographic history of each population predicts a depletion of rare deleterious variants in the range-edge population, but an enrichment for fixed ones, consistent with the bottleneck effect. However, the demographic history of the range-edge population predicts a small net decrease in per-individual fitness. Consistent with this prediction, the range-edge population is not impaired in its growth and survival measured in a common garden experiment. We further observe that the allelic diversity at the self-incompatibility locus, which ensures strict outcrossing and evolves under negative frequency-dependent selection, has remained unchanged. Genomic footprints indicative of selective sweeps are broader in the Northern population but not less frequent. We conclude that the outcrossing species A. lyrata ssp. petraea shows a strong resilience to the effect of range expansion.
Development and clinical validation of a blood test for early detection of colorectal adenomas and cancer.
Authors: Shai Friedland, Jennifer Y. Pan, Drew Watson, Yu Chen, Ashish Nimgaonkar, Zulfiqar Gulzar, Pratyush Gupta, Alex Atkins, Jr-Ming Lai, Ben Hsieh, Stephen Su, Iris Ciu, Ploy Setthasap, John Sninsky, Rui Mei
Journal: Journal of Clinical Oncology (2021)

50 Background: Many of the 50,000 annual colorectal cancer (CRC) deaths can be attributed to 1/3 eligible Americans not following screening guidelines or approximately 1/2 of the population not adherent to the follow-up post-polypectomy guidelines. The new understanding of the natural history and shared etiology of adenomas and CRC inform integration of clinically relevant biomarkers. The two objectives of CRC screening and surveillance are early detection to improve survival and prevention of CRC through removal of adenomas using colonoscopy. Adenomas account for 98% of actionable colonoscopies. Stool tests have low sensitivity for advanced adenomas (AA, 24-42%). Methods: A prospective, blinded study was conducted at the VA Palo Alto Health Care System. Patients had blood drawn prior to colonoscopy. The test analyzes two biomarkers: circulating gastrointestinal epithelial cells and somatic mutations of cell-free DNA. The probability of advanced neoplasia was obtained by ordinal/nominal logistic regression methods together with SEER-incidence rate and prior history of AA on a training set of 346 subjects. The cutpoint for the quantitative score was fixed and the remaining 112 subjects were tested. Results: Interim results for 458 patients with no prior diagnosis of colorectal cancer (CRC) are presented. The cohort included both screening (239) and surveillance (219) subjects. Indications for colonoscopy were 86% asymptomatic and 14% with symptoms or positive-FIT. Balanced distribution of roughly 3/4 th subjects in each disease category were randomly selected for training and algorithm development and the remaining 1/4 th subjects were used for validation. A cutpoint was selected to obtain a test specificity (non-neoplastic finding or negative colonoscopy) of 90% resulting in a sensitivity of 100% and 80.0% for detection of CRC and advanced neoplasia (AN = CRC+AA), respectively, on the training subjects. The area under the ROC curve is 0.91. Validation using the fixed cutpoint and 112 test subjects achieved 91.4% specificity and 100% and 75.0% sensitivity for CRC and AN. Conclusions: This blood test has high sensitivity for colorectal advanced neoplasia while retaining high specificity. The quantitative nature of the score has the potential to enable stratification of patients for screening or post-polypectomy surveillance colonoscopy. [Table: see text]
Characteristics of genomic alterations in circulating tumor DNA (ctDNA) in patients (Pts) with advanced gastrointestinal (GI) cancers in nationwide large-scale ctDNA screening:SCRUM-Japan Monstar-Screen.
Authors: Yoshiaki Nakamura, Takao Fujisawa, Shigenori Kadowaki, Naoki Takahashi, Masahiro Goto, Kazuhiro Yoshida, Takeshi Kawakami, Taito Esaki, Eiji Oki, Naohiro Nishida, Tomohiro Nishina, Yoshito Komatsu, Takashi Ohta, Naomi Kuramoto, Satoshi Horasawa, Yasutoshi Sakamoto, Hiroya Taniguchi, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2021)

106 Background: Analysis of ctDNA has been utilized in pts with advanced GI cancer for identification of genomic alterations for targeted therapy. However, the characteristics of ctDNA genomic alterations of GI cancers compared to non-GI cancers remains unclear. Methods: Pts with advanced solid tumors were eligible in MONSTAR-SCREEN, a nationwide ctDNA screening project in Japan. Plasma samples were analyzed by an NGS-based 70-gene ctDNA assay, FoundationOne Liquid (F1L) at a CLIA-certified and CAP-accredited laboratory since Jul 2019. For treatment-naïve pts, tumor tissue samples were analyzed by FoundationOne CDx (F1CDx), a 324-gene tissue-based panel. Results: As of Jun 18 2020, out of enrolled 540 pts with advanced solid tumor, 470 pts, consisting of 133 with advanced GI cancers (67 colorectal, 48 gastric, 14 esophageal, 2 gastrointestinal tumor (GIST) and 2 small intestinal) and 337 non-GI cancers (103 hepatobiliary and pancreatic, 70 genitourinary, 64 breast, 46 head and neck, 33 gynecologic, and 21 skin), had an available ctDNA result. Sequencing success rate was similar between GI and non-GI cancers (91.7% vs. 89.3%, P = 0.50). GI cancers had a significantly higher ctDNA level (maximum variant allele fraction) than non-GI cancers (median, 11.8% vs. 0.57%; P = 1.6E-7). The most frequently altered genes were TP53 (73%), APC (73%), KRAS (30%), BRAF (15%), and PIK3CA (12%) in colorectal cancer, TP53 (44%), KRAS (19%), PIK3CA (15%), ATM (10%), and ERBB2 (10%) in gastric cancer, and TP53 (79%), ATM (21%), ERBB2 (21%) in esophageal cancer. Mutations in genes in pathways related to RAS/RAF/MEK (39.1 % vs. 21.4 %, P = 1.8E-4), receptor tyrosine kinase (20.3% vs 11.9%, P = 0.027), p53 (66.2% vs 49.6%, P = 0.0014), and Wnt (41.4% vs 4.7%, P = 4.4E-21) were significantly enriched in GI cancers compared to non-GI cancers. Tumor tissue samples were analyzed using F1CDx for 63 treatment-naïve pts, in which 51 (31.3%) of 132 alterations identified by F1L were not detected by F1CDx. Conclusions: GI cancers had higher ctDNA levels and distinct characteristics of ctDNA genomic alterations from non-GI cancers with an enrichment in several oncogenic pathways. One-third of ctDNA alterations were detected in only ctDNA, indicating the potential of ctDNA analysis to identify heterogenous genomic alterations in advanced GI cancer. Clinical trial information: UMIN000036749.
Tissue‐Resident Memory CD8+ T Cells From Skin Differentiate Psoriatic Arthritis From Psoriasis
Authors: Emmerik F. Leijten, Tessa S. van Kempen, Michel A. Olde Nordkamp, Juliette N. Pouw, Nienke J. Kleinrensink, Nanette L. Vincken, Jorre Mertens, Deepak M. W. Balak, Fleurieke H. Verhagen, Sarita A. Hartgring, Erik Lubberts, Janneke Tekstra, Aridaman Pandit, Timothy R. Radstake, Marianne Boes
Journal: Arthritis & Rheumatology (2021)

To compare immune cell phenotype and function in psoriatic arthritis (PsA) versus psoriasis in order to better understand the pathogenesis of PsA.In-depth immunophenotyping of different T cell and dendritic cell subsets was performed in patients with PsA, psoriasis, or axial spondyloarthritis and healthy controls. Subsequently, we analyzed cells from peripheral blood, synovial fluid (SF), and skin biopsy specimens using flow cytometry, along with high-throughput transcriptome analyses and functional assays on the specific cell populations that appeared to differentiate PsA from psoriasis.Compared to healthy controls, the peripheral blood of patients with PsA was characterized by an increase in regulatory CD4+ T cells and interleukin-17A (IL-17A) and IL-22 coproducing CD8+ T cells. One population specifically differentiated PsA from psoriasis: i.e., CD8+CCR10+ T cells were enriched in PsA. CD8+CCR10+ T cells expressed high levels of DNAX accessory molecule 1 and were effector memory cells that coexpressed skin-homing receptors CCR4 and cutaneous lymphocyte antigen. CD8+CCR10+ T cells were detected under inflammatory and homeostatic conditions in skin, but were not enriched in SF. Gene profiling further revealed that CD8+CCR10+ T cells expressed GATA3, FOXP3, and core transcriptional signature of tissue-resident memory T cells, including CD103. Specific genes, including RORC, IFNAR1, and ERAP1, were up-regulated in PsA compared to psoriasis. CD8+CCR10+ T cells were endowed with a Tc2/22-like cytokine profile, lacked cytotoxic potential, and displayed overall regulatory function.Tissue-resident memory CD8+ T cells derived from the skin are enhanced in the circulation of patients with PsA compared to patients with psoriasis alone. This may indicate that aberrances in cutaneous tissue homeostasis contribute to arthritis development.
AB0193 Electromyography and nerve conduction in patients on regular haemodialysis
Authors: AF El Ghobarey, W Kamel, E Abdel Mobdy
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> The evolution of nerve conduction studies and EMG was determined following 30 patients with chronic renal failure maintained on regular haemodialysis for 12 men for 12 months. <h3>Methods</h3> Eighteen different electroneurographic (ENG) indices were compared in three groups of patients of different dialysis duration. <h3>Results</h3> No relationship was found between neuropathy and duration of haemodialysis. No correlation was found between all ENG indices and the age and sex. Also, nerve conduction was independent of the disease underlying renal failure. The side of arteriovenous vascular access had no statistically significant effect on motor nerve conduction studies in the upper extremities. ENG indices showed no significant correlation with serum creatinine, PTH, and beta 2 microglobulin. Mean motor nerve conduction velocity (MNCV) and distal latency (DL) were significantly different (decreased and increased respectively) at the beginning of the study and one year later for the median, ulnar, and common peroneal nerves on both sides. The change was more in patients with low Kt/V (a depuration index) than those with high Kt/V. <h3>Conclusion</h3> At the end of the study all patients had had peripheral polyneuropathy, 8 patients (26.7%) had got CTS, and 8 patients (26.7%) had subclinical median mononeuropathy. Axonal neuropathy was present in 100% of patients and demyelinating neuropathy was present in 8 patients (26.7%).
Microsatellite instability in colorectal cancer: An analysis of the National Cancer Database.
Authors: Kamelah Abushalha, Sawsan Abulaimoun, Sarah J Aurit, Erin Jenkins, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2021)

134 Background: High-frequency microsatellite instability (MSI-H) accounts for roughly 15% of all cases of colorectal cancer (CRC). Studies suggest a significant non-adherence to routine MSI testing in patients diagnosed with CRC despite universal guidelines. Methods: We used the NCDB to identify adults with MSI-H status CRC from 2010-2015 with the following histologic subtypes: mucinous and not otherwise specified adenocarcinoma, and medullary carcinoma. The primary site was localized to the right colon, left colon, and rectum; demographic factors, clinicopathologic features, and treatments were identified. Patients were stratified by site and discrete and continuous variable comparisons were made using the chi-square and Mann-Whitney test, respectively. Survival was examined with the Kaplan-Meier method and a Cox proportional hazards regression model. A logistic regression model was used to examine MSI status. All analyses were conducted with SAS version 9.4. Results: A total of 5364 patients were identified and stratified by site into 3 groups: right colon (n = 4004, 74.6%), left colon (n = 890, 16.59%) and rectum (n = 470, 8.76%). Compared to the left colon and rectum, right colon patients were more likely to be older females with larger tumors and less likely to receive chemoradiation. After adjusting for all else, we found statistical evidence that female vs. male gender (OR = 1.47; 95% CI: 1.24 to 1.73), Black vs. White race (OR = 0.61; 0.45 to 0.83), left vs. right colon (OR = 0.33, 0.27 to 0.41), rectum vs. right colon (OR = 0.08, 0.05 to 0.13), mucinous adenocarcinoma vs. adenocarcinoma (OR = 2.37, 1.92 to 2.93), medullary carcinoma vs. adenocarcinoma (OR = 8.86, 4.56 to 17.22), positive vs. negative k-RAS mutation (OR = 0.49, 0.41 to 0.59), and positive vs. negative CEA status (OR = 0.79, 0.66 to 0.94) were factors associated with MSI-H status. Improved survival was associated were Hispanic white race, stage 1, and free surgical margins within a multivariable context. Factors associated with poor survival: increased Charlson/Deyo score, advanced stage, lymphovascular invasion, and positive CEA status. Conclusions: In settings where resources are scarce and universal testing is not possible, there is a benefit from MSI testing in female patients, those with right-sided colon cancer, mucinous adenocarcinoma, and medullary carcinoma.
Early Worsening of Diabetic Nephropathy in Type 2 Diabetes After Rapid Improvement in Chronic Severe Hyperglycemia
Authors: Tim Cundy, Andrew Holden, Elizabeth Stallworthy
Journal: Diabetes Care (2021)

In people with chronically severe hyperglycemia, a paradoxical deterioration of microvascular complications may occur if glycemic control is improved very rapidly. This “early worsening” is well documented for retinopathy (1) and painful neuropathy (2), but not nephropathy.

We describe three men and one woman (ages 38–61 years) who presented with marked hyperglycemia. Type 2 diabetes had not previously been recognized in three cases, but the presence of retinopathy and signs of neuropathy indicated diabetes of at least 5 years’ duration. In the fourth case, diabetes had been diagnosed 6 years earlier, but the subject had declined treatment. In case 1, diabetes was recognized coincident with Hodgkin lymphoma, which was successfully treated with nonnephrotoxic chemotherapy. In case 2, diabetes was recognized at presentation with sepsis and acute kidney injury that rapidly improved with volume repletion and antibiotic treatment. None were smokers, had cardiovascular disease, or had a family history of renal disease. At presentation mean values were as follows: BMI 25.0 kg/m2, A1C 118 mmol/mol (12.9%), and estimated glomerular filtration rate (eGFR) 70 mL/min/1.73 m2. One subject was treated with insulin from diagnosis; one took insulin for 3 months, then transferred to oral hypoglycemic agents; and two were treated only with …
How Far Should We Explore Hypospadias? Next-generation Sequencing Applied to a Large Cohort of Hypospadiac Patients
Authors: Vuthy Ea, Anne Bergougnoux, Pascal Philibert, Nadège Servant-Fauconnet, Alice Faure, Jean Breaud, Laura Gaspari, Charles Sultan, Françoise Paris, Nicolas Kalfa
Journal: European Urology (2021)
The Prognostic Value of Time in Range in Type 2 Diabetes
Authors: Elizabeth Selvin
Journal: Diabetes Care (2021)

Continuous glucose monitoring (CGM) is the recommended approach to the assessment of hypoglycemia and glycemic variability in the setting of type 1 diabetes (1). The latest generation of CGM systems measure glucose every minute or every few minutes, with devices providing ∼1,300 to up to ∼20,000 measurements per person for a 14-day wear period. With this many measurements per person, the question arises of how to summarize the data in the most clinically useful manner and best communicate the results to patients. Time in range has emerged as a CGM metric with clinical utility in the management of type 1 diabetes (2,3).

Time in range is a relatively simple CGM metric, defined as the percent of time spent with glucose values within a target range, usually 70–180 mg/dL (3.9–10 mmol/L), although the target can be individualized. Time in range is automatically calculated and included in CGM system reports, along with percentage of time spent in hypo- and hyperglycemic glucose ranges (i.e., below or above target), average glucose, standard deviation, and coefficient of variation. As costs have come down and device accuracy has improved, the adoption of CGM has increased, with up to 20–30% of some U.S. patient populations with type 1 diabetes currently using the technology (4).

In patients with type 2 diabetes, the benefits and role of CGM in clinical management are less clear than in patients with type 1 diabetes. American Diabetes Association guidelines state that CGM may have a role in selected patients with type 2 diabetes, primarily those who are taking multiple daily injections of insulin (5). There …
CEACAM7 Is an Effective Target for CAR T-cell Therapy of Pancreatic Ductal Adenocarcinoma
Authors: Deepak Raj, Maria Nikolaidi, Irene Garces, Daniela Lorizio, Natalia M. Castro, Sabrina G. Caiafa, Kate Moore, Nicholas F. Brown, Hemant M. Kocher, Xiaobo Duan, Brad H. Nelson, Nicholas R. Lemoine, John F. Marshall
Journal: Clinical Cancer Research (2021)

To investigate whether CEACAM7 represents a novel therapeutic target for treating pancreatic ductal adenocarcinoma (PDAC) and to generate CEACAM7-targeting CAR T cells to test this hypothesis.We identified CEACAM7 (CGM2), a member of the CEA family of proteins with expression restricted to the colon and pancreas, as a potential CAR T-cell target for PDAC. We probed a panel of PDAC tumor sections as well as patient-derived PDAC cell cultures for CEACAM7 expression. We generated CAR-targeting CEACAM7, and assessed antitumor efficacy of CEACAM7 CAR T cells using in vitro and in vivo models.We show here that CEACAM7 is expressed in a large subset of PDAC tumors, with low to undetectable expression in all normal tissues tested. CEACAM7 is also expressed in primary PDAC cultures isolated from patient-derived tumors, with high expression within the cancer stem cell-enriched subset. CAR T cells targeting CEACAM7 are capable of targeting antigen-expressing tumor cells, and mediate remission in patient-derived xenograft tumors.We identify CEACAM7 as a potential therapeutic target in PDAC and describe the development of CEACAM7-targeted CAR T cells with efficacy against PDAC.