tbuckley/cabot-search huggingface dataset:
Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma
Authors: Seok-Young Kim, Sang-Min Kim, Sumin Lim, Ji Yeon Lee, Su-Jin Choi, San-Duk Yang, Mi Ran Yun, Chang Gon Kim, Seo Rin Gu, Chaewon Park, A-Young Park, Sun Min Lim, Seong Gu Heo, HyunKi Kim, Byoung Chul Cho
Journal: Clinical Cancer Research (2021)

Patient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targeted therapies in individual patients and to identify effective anticancer therapies for novel molecular targets.Eighty-four organoids were established from patients with advanced lung adenocarcinoma. Formalin-fixed, paraffin-embedded tumor specimens from corresponding patients were analyzed by whole-exome sequencing (n = 12). Organoids were analyzed by whole-exome sequencing (n = 61) and RNA sequencing (n = 55). Responses to mono or combination targeted therapies were examined in organoids and organoid-derived xenografts.PDOs largely retained somatic alterations including driver mutations of matching patient tumors. PDOs were able to recapitulate progression-free survival and objective responses of patients with non-small cell lung cancer receiving clinically approved tyrosine kinase inhibitors. PDOs recapitulated activity of therapeutic strategies under clinical investigation. YUO-071 harboring an EGFR exon 19 deletion and a BRAF G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an EGFR L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to identify effective therapies for novel molecular targets by demonstrating the efficacy of poziotinib against ERBB2 exon 20 insertions and pralsetinib against RET fusions.We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool, which can assist clinical decision making and accelerate development of therapeutic strategies.
AB0349 NEUTROPHIL-TO-LYMPHOCYTE RATIO, PLATELET-TO-LYMPHOCYTE RATIO AND MEAN PLATELET VOLUME IN LUPUS NEPHRITIS
Authors: T. Knežević, I. Padjen, S. Bulimbašić, M. Ćorić, V. Ivković, M. Laganović, B. Anić
Journal: Annals of the Rheumatic Diseases (2021)

Background: A number of blood count parameters are associated with inflammatory and autoimmune diseases. There is discordant evidence whether neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and mean platelet volume (MPV) might reflect inflammatory response and have prognostic value in SLE patients. However, the studies examining the potential role of these markers in LN are missing. Objectives: To examine NLR, PLR and MPV at the time of biopsy in patients with LN and evaluate their association with prognosis. Methods: In this retrospective study we analyzed the demographic, histologic, laboratory and clinical characteristics of patients with biopsy-proven LN diagnosed between 2011 and 2020. All patients met the 1997 revised American College of Rheumatology classification criteria for SLE. Complete remission was defined as proteinuria &lt;0.5 g/day and serum creatinine within 10% from baseline, and partial remission as more than 50% reduction in proteinuria to sub-nephrotic levels and serum creatinine within 10% from baseline. Results: We have included 55 patients (80% women) with biopsy-proven LN (age at biopsy 38±13 years). On renal histology, one patient was class I LN, two patients were class II, 7 were class III, 5 were class III+V, 23 were class IV, two were class IV+V, 11 class VI and 4 had other features. Median baseline NLR was 3.64 (IQR: 1.85, 6.93), PLR was 167 (IQR: 116, 300) and MPV was 10.0 (IQR: 9.2, 10.8). There were no differences in any of the three parameters between different classess of LN (all p&gt;0.05). Eighteen patients achieved complete remission (CR), 16 partial remission and 21 did not achieve remission. None progressed to ESRD and two patients died, both from sepsis. There no differences in NLR, PLR and MPV at the time of biopsy between group which achieved CR/PR vs. no remission (all p&gt;0.05; Figure 1). We constructed a thorough multivariate regression model which showed that neither NLR, PLR or MPV are predictors of renal remission in LN. Conclusion: NLR, PLR and MPV are not useful prognostic markers in predicting renal remission in LN. References: [1]Hartmann LT, et al. Open Rheumatol J. 2018 Aug 31;12:129-138. [2]Chen SY, et al. J Res Med Sci. 2018 May 30;23:48. [3]Zhao CN, et al. Rheumatol Int. 2018 Sep;38(9):1635-1641. Disclosure of Interests: None declared
Exposure to Family Member Incarceration and Adult Well-being in the United States
Authors: Ram Sundaresh, Youngmin Yi, Tyler D. Harvey, Brita Roy, Carley Riley, Hedwig Lee, Christopher Wildeman, Emily A. Wang
Journal: JAMA Network Open (2021)

More than half of the adult population in the United States has ever had a family member incarcerated, an experience more common among Black individuals. The impacts of family incarceration on well-being are not fully understood.
AB0192 EVALUATION OF TEMPOROMANDIBULAR JOINT INVOLVEMENT IN PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: M. Brahem, A. Ben Salem, H. Hachfi, R. Sarraj, S. Abedallatif, R. Tekaya, C. Baccouche, Y. Mohamed
Journal: Annals of the Rheumatic Diseases (2021)

Background: Rheumatoid Arthritis (RA) is the most common chronic inflammatory disease usually involves peripheral joints with a symmetric distribution. The temporomandibular joint (TMJ) is seldom joint to be affected first in the disease course. Objectives: The Aim of our study is to describe and to assess the prevalence of temporomandibular joint (TMJ)disorders in patients with Rheumatoid arthritis (RA). Methods: A cross sectional study including RA patients, which consulted or were hospitalized in Rheumatology department in Taher Sfar Hospital of Mahdia Tunisia, during a period of 10 months. The diagnosis of the RA was secured by the ACR/EULAR 2010, Rheumatoid Arthritis Classification Criteria. The clinical TMJ examination was performed by a trained dentist in the same hospital. We assessed TMJ pain with VAS (visual analog scale) which varies from 0 to 10. The following key parameters were evaluated: The pain on the TMJs by bilateral palpation; The TMJ sounds (clicking or crepitus) during opening closing of the mandible; dysfunction and movement alterations. Clinical and sociodemographic parameters were also determined. Results: Our study included 51 patients with an average age of 51.11 years ±12.4 [21-74years]. 50patients (92.6%of cases) were women and 8 patients (14.8%) were diabetic. Only one patient was a smoker. The mean duration of RA was 10.7 years 7.7± [10months-35years]. Rheumatoid factor (RF) was positive in 25 Patients (46.3%of cases). Anti-citrullinated peptide antibody (ACPA) was positive in 32 patients (59.3 %).41patients (75.4%) had radiological impairments and 28 (51.9%) had specific deformations of RA. The average disease activity score (DAS28-VS) and (DAS28-CRP) were respectively 4.1±1.5 [1.4-7.3] and 3.4±1.5 [1.24-6.71]. TMJ pain was present in 29 patients (56.9 %) which67.7% appeared before ten years. 5 patients (16.7%) had VAS more than 7 that mean a severe pain. TMJ involvement was bilateral in 64.3% and unilateral in 35.7 %. Functional difficulties were detected in 22 patients (44.9 %). TMJ examination had also revealed a limitation of mouth opening in 11 patients (21.2 %), a movement alteration in 13 patients (27.79 %), a clicking in joint mobility in 13 patients (81.3 %) and joint crepitus in 1 patient (6.3%). Disease duration was associated with TMJ pain(p=0.05) and mobility alterations (p=0.04). Functional difficulties of the TMJ were correlated with DAS28 (p=0.02). In our study we found also that duration of corticosteroid therapy had in impact on TMJ pain (p=0.01), functional difficulties (p=0.01) and movements alterations (p=0.004). Conclusion: TMJ is very rare to be affected in the early phase of the disease, thus patient may develop signs and symptoms in the course of time. Our study showed the frequency of TMJ disorders and the most important factors were the activity of RA and the duration of the disease course. Disclosure of Interests: None declared
Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment
Authors: Francesca Polverino, Tianshi David Wu, Joselyn Rojas-Quintero, Xiaoyun Wang, Jonathan Mayo, Michael Tomchaney, Judy Tram, Samuel Packard, Duo Zhang, Kristan H. Cleveland, Elizabeth Cordoba-Lanus, Caroline A. Owen, Ashraf Fawzy, Greg L. Kinney, Craig P. Hersh, Nadia N. Hansel, Kevin Doubleday, Maor Sauler, Yohannes Tesfaigzi, Julie G. Ledford, Ciro Casanova, Jaroslaw Zmijewski, John Konhilas, Paul R. Langlais, Rick Schnellmann, Irfan Rahman, Meredith McCormack, Bartolome Celli
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Cigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, and emphysema, as well as systemic pathologies. Metformin is beneficial for protecting against aging-related diseases. Objectives: We sought to investigate whether metformin may ameliorate CS-induced pathologies of emphysematous chronic obstructive pulmonary disease (COPD). Methods: Mice were exposed chronically to CS and fed metformin-enriched chow for the second half of exposure. Lung, kidney, and muscle pathologies, lung proteostasis, endoplasmic reticulum (ER) stress, mitochondrial function, and mediators of metformin effects in vivo and/or in vitro were studied. We evaluated the association of metformin use with indices of emphysema progression over 5 years of follow-up among the COPDGene (Genetic Epidemiology of COPD) study participants. The association of metformin use with the percentage of emphysema and adjusted lung density was estimated by using a linear mixed model. Measurements and Main Results: Metformin protected against CS-induced pulmonary inflammation and airspace enlargement; small airway remodeling, glomerular shrinkage, oxidative stress, apoptosis, telomere damage, aging, dysmetabolism in vivo and in vitro; and ER stress. The AMPK (AMP-activated protein kinase) pathway was central to metformin's protective action. Within COPDGene, participants receiving metformin compared with those not receiving it had a slower progression of emphysema (−0.92%; 95% confidence interval [CI], −1.7% to −0.14%; P = 0.02) and a slower adjusted lung density decrease (2.2 g/L; 95% CI, 0.43 to 4.0 g/L; P = 0.01). Conclusions: Metformin protected against CS-induced lung, renal, and muscle injury; mitochondrial dysfunction; and unfolded protein responses and ER stress in mice. In humans, metformin use was associated with lesser emphysema progression over time. Our results provide a rationale for clinical trials testing the efficacy of metformin in limiting emphysema progression and its systemic consequences.
The Relationship Between Body Fat Distribution and Nonalcoholic Fatty Liver in Adults With Type 1 Diabetes
Authors: Erika B. Parente, Emma H. Dahlström, Valma Harjutsalo, Jussi Inkeri, Stefan Mutter, Carol Forsblom, Niina Sandholm, Daniel Gordin, Per-Henrik Groop
Journal: Diabetes Care (2021)

OBJECTIVE Obesity, which is associated with nonalcoholic fatty liver (NAFL), has increased among people with type 1 diabetes. Therefore, we explored the associations between body fat distribution and NAFL in this population. RESEARCH DESIGN AND METHODS This study included 121 adults with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study for whom NAFL was determined by magnetic resonance imaging. Body composition was assessed by dual-energy X-ray absorptiometry. Genetic data concerning PNPLA3 rs738409 and TM6SF2 rs58542926 were available as a directly genotyped polymorphism. Associations between body fat distribution, waist-to-height ratio (WHtR), BMI, and NAFL were explored using logistic regression. A receiver operating characteristic (ROC) curve was used to determine the WHtR and BMI thresholds with the highest sensitivity and specificity to detect NAFL. RESULTS Median age was 38.5 (33–43.7) years, duration of diabetes was 21.2 (17.9–28.4) years, 52.1% were women, and the prevalence of NAFL was 11.6%. After adjusting for sex, age, duration of diabetes, and PNPLA3 rs738409, the volume (P = 0.03) and percentage (P = 0.02) of visceral adipose tissue were associated with NAFL, whereas gynoid, appendicular, and total adipose tissues were not. The area under the curve between WHtR and NAFL was larger than BMI and NAFL (P = 0.04). The WHtR cutoff of 0.5 showed the highest sensitivity (86%) and specificity (55%), whereas the BMI of 26.6 kg/m2 showed 79% sensitivity and 57% specificity. CONCLUSIONS Visceral adipose tissue is associated with NAFL in adults with type 1 diabetes, and WHtR may be considered when screening for NAFL in this population.
Active stealth and self-positioning biomimetic vehicles achieved effective antitumor therapy
Authors: Yao-Sheng Li, Hong-Hui Wu, Xin-Chi Jiang, Tian-Yuan Zhang, Yi Zhou, Ling-Ling Huang, Pei Zhi, Yasuhiko Tabata, Jian-Qing Gao
Journal: Journal of Controlled Release (2021)
<i>JAMA</i> editor in chief steps down over controversial structural racism podcast
Authors: Janice Hopkins Tanne
Journal: BMJ (2021)

Howard Bauchner, the editor in chief of JAMA , will step down on 30 June in the fallout from a podcast and Twitter post about structural racism in US medicine.

The American Medical Association’s search committee for a new editor in chief will be chaired by a prominent African-American physician, Otis Brawley. He is Bloomberg distinguished professor of oncology and epidemiology at Johns Hopkins University and served as chief medical and scientific officer and executive vice president of the American Cancer Society. Previously he twice chaired a search committee for editor in chief of the journal Cancer .

The furore began with a JAMA podcast on 23 February that included a …
POS1226 THE COURSE OF CORONAVIRUS DISEASE 2019 (COVID-19) IN PATIENTS WITH SJOGREN’S SYNDROME TREATED WITH ANTI-CD20 MONOCLONAL ANTIBODY (RITUXIMAB)
Authors: E. Sokol, A. Torgashina, B. Chalcev, J. Khvan, O. Golovina
Journal: Annals of the Rheumatic Diseases (2021)

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) raised concern for the outcomes in people with different rheumatic diseases and management of these patients. There was an anxiety that biologic therapies, especially anti-B-cell depletion strategies, could lead to more severe disease course and lack of protective antibodies formation. Information about the course of COVID-19 in patients with certain rheumatic diseases is still lacking. Objectives: To examine clinical course of COVID-19 in patients with Sjogren’s syndrome treated with anti-CD20 monoclonal antibody (rituximab). Methods: Single center observational study. Diagnosis of SjS was based on ECR/EULAR 2016 criteria. COVID-19 diagnosis was based on positive PCR test even without clinical symptoms and/or typical clinical features (CT signs, fever and anosmia). Rituximab was administrated in two 1000 mg infusions 14 days apart for the 1 st course, then 500 mg every 6 months. Results: 19 patients were included, 18 women and 1 man. Median age was 55 years (29-70 years), and median rituximab treatment duration was 24 months (1-48 months). Five patients had concomitant RA (2 patients), SLAE (1 pt), Systemic sclerosis (2 patients). Patients with RA took baricitinib and methotrexate as well. 3 patients had MALT-lymphoma anamnesis (24, 38 and 24 months before the diagnosis of COVID-19). Only 3 patients had chronic ischemic heart disease and/or arterial hypertension. 12 patients were PCR positive, 6 negative and in 1 the test was not done. 11 patients had full and 4 partial B-cell depletion in peripheral blood. Five patients had &lt;20% lung involvement on CT, 2 patients – 20-40% and 4 patients – 40-60%. Three patients with 40-60% lung involvement required hospitalization due to marked shortness of breath and long febrile period, 2 of them received anti-IL6 treatment and neither of them required mechanical lung ventilation (either non-invasive or invasive). Seventeen patients were treated at home and recovered in 10-24 days. Anti-SARS-CoV-2 IgG were measured in 9 patients, 6 (66.7%) of them were positive. Conclusion: It seems that neither SjS itself nor anti-CD20 therapy predisposes patients to severe course of COVID-19. Presumably risk factors such as age, diabetes or anamnesis of cardiovascular diseases have far more significant impact on COVID-19 severity. Data hints that anti-CD20 therapy might negatively affect the formation of specific anti-SARS-CoV-2 humoral immunity, but further investigation is required to determine that with any degree of certainty. Disclosure of Interests: None declared
Darolutamide Potentiates the Antitumor Efficacy of a PSMA-targeted Thorium-227 Conjugate by a Dual Mode of Action in Prostate Cancer Models
Authors: Stefanie Hammer, Andreas Schlicker, Sabine Zitzmann-Kolbe, Simon Baumgart, Urs B. Hagemann, Arne Scholz, Bernard Haendler, Pascale Lejeune, Jenny Karlsson, Christine Ellingsen, Hartwig Hennekes, Carsten H. Nielsen, Mark U. Juul, Dominik Mumberg, Christoph A. Schatz
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Androgen receptor (AR) inhibitors are well established in the treatment of castration-resistant prostate cancer and have recently shown efficacy also in castration-sensitive prostate cancer. Although most patients respond well to initial therapy, resistance eventually develops, and thus, more effective therapeutic approaches are needed. Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and presents an attractive target for radionuclide therapy. Here, we evaluated the efficacy and explored the mode of action of the PSMA-targeted thorium-227 conjugate (PSMA-TTC) BAY 2315497, an antibody-based targeted alpha-therapy, in combination with the AR inhibitor darolutamide. Experimental Design: The in vitro and in vivo antitumor efficacy and mode of action of the combination treatment were investigated in preclinical cell line–derived and patient-derived prostate cancer xenograft models with different levels of PSMA expression. Results: Darolutamide induced the expression of PSMA in androgen-sensitive VCaP and LNCaP cells in vitro, and the efficacy of darolutamide in combination with PSMA-TTC was synergistic in these cells. In vivo, the combination treatment showed synergistic antitumor efficacy in the low PSMA-expressing VCaP and in the high PSMA-expressing ST1273 prostate cancer models, and enhanced efficacy in the enzalutamide-resistant KUCaP-1 model. The treatments were well tolerated. Mode-of-action studies revealed that darolutamide induced PSMA expression, resulting in higher tumor uptake of PSMA-TTC, and consequently, higher antitumor efficacy, and impaired PSMA-TTC–mediated induction of DNA damage repair genes, potentially contributing to increased DNA damage. Conclusions: These results provide a strong rationale to investigate PSMA-TTC in combination with AR inhibitors in patients with prostate cancer.
Abcc1 and Ggt5 support lymphocyte guidance through export and catabolism of <i>S</i> -geranylgeranyl- <scp>l</scp> -glutathione
Authors: Antonia E. Gallman, Finn D. Wolfreys, David N. Nguyen, Moriah Sandy, Ying Xu, Jinping An, Zhongmei Li, Alexander Marson, Erick Lu, Jason G. Cyster
Journal: Science Immunology (2021)

This work establishes how P2RY8 ligand is exported and degraded to regulate lymphocyte behavior in lymphoid follicles and bone marrow.
A nanofibrous encapsulation device for safe delivery of insulin-producing cells to treat type 1 diabetes
Authors: Xi Wang, Kristina G. Maxwell, Kai Wang, Daniel T. Bowers, James A. Flanders, Wanjun Liu, Long-Hai Wang, Qingsheng Liu, Chengyang Liu, Ali Naji, Yong Wang, Bo Wang, Jing Chen, Alexander U. Ernst, Juan M. Melero-Martin, Jeffrey R. Millman, Minglin Ma
Journal: Science Translational Medicine (2021)

Transplantation of stem cell-derived β (SC-β) cells represents a promising therapy for type 1 diabetes (T1D). However, the delivery, maintenance, and retrieval of these cells remain a challenge. Here, we report the design of a safe and functional device composed of a highly porous, durable nanofibrous skin and an immunoprotective hydrogel core. The device consists of electrospun medical-grade thermoplastic silicone-polycarbonate-urethane and is soft but tough (~15 megapascal at a rupture strain of >2). Tuning the nanofiber size to less than ~500 nanometers prevented cell penetration while maintaining maximum mass transfer and decreased cellular overgrowth on blank (cell-free) devices to as low as a single-cell layer (~3 micrometers thick) when implanted in the peritoneal cavity of mice. We confirmed device safety, indicated as continuous containment of proliferative cells within the device for 5 months. Encapsulating syngeneic, allogeneic, or xenogeneic rodent islets within the device corrected chemically induced diabetes in mice and cells remained functional for up to 200 days. The function of human SC-β cells was supported by the device, and it reversed diabetes within 1 week of implantation in immunodeficient and immunocompetent mice, for up to 120 and 60 days, respectively. We demonstrated the scalability and retrievability of the device in dogs and observed viable human SC-β cells despite xenogeneic immune responses. The nanofibrous device design may therefore provide a translatable solution to the balance between safety and functionality in developing stem cell-based therapies for T1D.
Nanoparticles and trained immunity: Glimpse into the future
Authors: Susana Magadán, Idoia Mikelez-Alonso, Francisco Borrego, África González-Fernández
Journal: Advanced Drug Delivery Reviews (2021)

Emerging evidences show that innate immune cells can display changes in their functional programs after infection or vaccination, which lead to immunomodulation (increased or reduced responsiveness) upon secondary activation to the same stimuli or even to a different one. Innate cells acquire features of immunological memory, nowadays using the new term of "trained immunity" or "innate immune memory", which is different from the specific memory immune response elicited by B and T lymphocytes. The review focused on the concept of trained immunity, mostly on myeloid cells. Special attention is dedicated to the pathogen recognition along the evolution (bacteria, plants, invertebrate and vertebrate animals), and to techniques used to study epigenetic reprogramming and metabolic rewiring. Nanomaterials can be recognized by immune cells offering a very promising way to learn about trained immunity. Nanomaterials could be modified in order to immunomodulate the responses ad hoc. Many therapeutic possibilities are opened, and they should be explored.