tbuckley/cabot-search huggingface dataset:
Five Year Survival Update From KEYNOTE-010: Pembrolizumab Versus Docetaxel for Previously Treated, Programmed Death-Ligand 1–Positive Advanced NSCLC
Authors: Roy S. Herbst, Edward B. Garon, Dong-Wan Kim, Byoung Chul Cho, Radj Gervais, Jose L. Perez-Gracia, Ji-Youn Han, Margarita Majem, Martin D. Forster, Isabelle Monnet, Silvia Novello, Matthew A. Gubens, Michael Boyer, Wu-Chou Su, Ayman Samkari, Erin H. Jensen, Julie Kobie, Bilal Piperdi, Paul Baas
Journal: Journal of Thoracic Oncology (2021)

In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in patients with previously treated, advanced NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% and ≥1%. We report 5-year efficacy and safety follow-up for the KEYNOTE-010 study.Patients were randomized to pembrolizumab 2 mg/kg or 10 mg/kg once every 3 weeks or docetaxel 75 mg/m2 once every 3 weeks for up to 35 cycles (2 y). Patients who completed pembrolizumab treatment and subsequently had recurrence could receive second-course pembrolizumab for up to 17 cycles (1 y). Pembrolizumab doses were pooled in this analysis.A total of 1034 patients were randomized (pembrolizumab, n = 691; docetaxel, n = 343). Median study follow-up was 67.4 months (range: 60.0‒77.9). The hazard ratio (95% confidence interval) for OS was 0.55 (0.44‒0.69) for patients with PD-L1 TPS ≥50% and 0.70 (0.61‒0.80) with PD-L1 TPS ≥1%. The 5-year OS rates for pembrolizumab versus docetaxel were 25.0% versus 8.2% in patients with PD-L1 TPS ≥50% and 15.6% versus 6.5% with PD-L1 TPS ≥1%. Among 79 patients who completed 35 cycles/2 years of pembrolizumab, the OS rate 3 years after completion (∼5 y from randomization) was 83.0%. A total of 21 patients received second-course pembrolizumab; 11 (52.4%) had an objective response after starting the second course and 15 (71.4%) were alive at data cutoff. Exploratory biomarker analysis revealed that higher tissue tumor mutational burden (≥175 mutations per exome) was associated with improved outcomes with pembrolizumab.Pembrolizumab continued to provide long-term benefit than docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1%. Our findings confirm pembrolizumab as a standard-of-care treatment in the second-line or later setting.
A Biallelic Frameshift Mutation in Nephronectin Causes Bilateral Renal Agenesis in Humans
Authors: Lei Dai, Jingzhi Li, Liangqun Xie, Weinan Wang, Yang Lu, Mingkun Xie, Jingrui Huang, Kuifang Shen, Hui Yang, Chenlin Pei, Yanhua Zhao, Weishe Zhang
Journal: Journal of the American Society of Nephrology (2021)

Bilateral renal agenesis (BRA) is a lethal con genital anomaly caused by the failure of normal development of both kidneys early in embryonic development. Oligohydramnios on fetal ultrasonography reveals BRA. Although the exact causes are not clear, BRA is associated with mutations in many renal development genes. However, molecular diagnostics do not pick up many clinical patients. Nephronectin (NPNT) may be a candidate protein for widening diagnosis. It is essential in kidney development, and knockout of Npnt in mice frequently leads to kidney agenesis or hypoplasia.A consanguineous Han family experienced three cases of induced abortion in the second trimester of pregnancy, due to suspected BRA. Whole-exome sequencing (WES)-based homozygosity mapping detected underlying genetic factors, and a knock-in mouse model confirmed the renal agenesis phenotype.WES and evaluation of homozygous regions in II:3 and II:4 revealed a pathologic homozygous frameshift variant in NPNT (NM_001184690:exon8:c.777dup/p.Lys260*), which leads to a premature stop in the next codon. The truncated NPNT protein exhibited decreased expression, as confirmed in vivo by the overexpression of WT and mutated NPNT. A knock-in mouse model homozygous for the detected Npnt mutation replicated the BRA phenotype.A biallelic loss-of-function NPNT mutation causing an autosomal recessive form of BRA in humans was confirmed by the corresponding phenotype of knock-in mice. Our results identify a novel genetic cause of BRA, revealing a new target for genetic diagnosis, prenatal diagnosis, and preimplantation diagnosis for families with BRA.
AB0534 THE IMPACT OF AXIAL INVOLVEMENT ON ACR RESPONSE IN PATIENTS WITH PSORIATIC ARTHRITIS: RESULTS OF SUBANALYSIS OF THE PATERA STUDY
Authors: T. Korotaeva, I. Gaydukova, V. Mazurov, A. Samtsov, V. Khayrutdinov, A. Bakulev, A. Kundzer, N. Soroka, A. Eremeeva
Journal: Annals of the Rheumatic Diseases (2021)

Background: Inflammatory back pain (IBP) is a common symptom of axial disease in patients with psoriatic arthritis (PsA). The reported prevalence of axial disease in patients with PsA is quite variable and must be taken into account while choosing treatment strategy. Netakimab (NTK) is an anti-interleukin-17A monoclonal antibody approved for psoriasis, ankylosing spondylitis, PsA in Russia and Belarus. Objectives: A subanalysis was aimed to investigate the ACR (American College of Rheumatology) 20/50/70 response rate in PsA patients with/without the axial disease, defined by the presence of IBP according to self-reported ASAS IBP criteria, 2009 at baseline. Methods: PATERA is an ongoing phase 3 international double-blind, placebo-controlled clinical study ( NCT03598751 ). 194 adult patients with PsA (CASPAR criteria, 2006) with inadequate response to csDMARD or one TNFi, were randomly assigned to receive NTK 120mg or placebo at weeks 0,1,2,4,6,8,10,14,18,22. The ACR response was calculated in NTK-treated patients with IBP (IBP(+)) and NTK-treated patients without IBP (IBP(-)) according to self-reported ASAS IBP criteria, 2009. Patients with missing values for categorical variables were considered as non-responders in the analysis. Results: 97 PsA patients (N=54 IBP(+), N=43 IBP(-)) received NTK. Both subpopulations were comparable in gender, age, and PsA activity at baseline. There were no significant differences in ACR20 achievement between the groups (Figure 1). The percentage of patients with ACR50 was significantly (p&lt;0.05) higher in the IBP(-) subpopulation at weeks 4-20 (data not shown), but not at week 24 with 63% IBP(+) and 79% IBP(-) responders (p≥0.05). Similarly, IBP(+) patients had a lower frequency of ACR70 response (Figure 1). Conclusion: NTK is effective in PsA treatment irrespectively of the presence of axial disease. Both IBP(-) and IBP(+) subpopulations achieved ACR20/50/70 as well, however, the benefit in IBP(-) patients was more pronounced. Figure 1 ACR response rates Acknowledgements: This study was sponsored by JSC BIOCAD. Disclosure of Interests: Tatiana Korotaeva Speakers bureau: Abbvie, Biocad, Eli Lilly, Johnson &amp; Johnson, Janssen, Novartis, Pfizer, UCB, Inna Gaydukova Speakers bureau: Abbvie, Biocad, Eli Lilly, MSD, Novartis, Pfizer, Sandoz, V Mazurov: None declared., Aleksey Samtsov: None declared., Vladislav Khayrutdinov: None declared., Andrey Bakulev: None declared., Alena Kundzer: None declared., Nikolaj Soroka: None declared., Anna Eremeeva Employee of: Biocad.
HIV pre-exposure prophylaxis for men who have sex with men in west Africa: a multicountry demonstration study
Authors: Christian Laurent, Bintou Dembélé Keita, Issifou Yaya, Gwenvael Le Guicher, Luis Sagaon-Teyssier, Mawuényégan K Agboyibor, Alou Coulibaly, Issa Traoré, Jean-Baptiste Malan, Irith De Baetselier, August Eubanks, Lucas Riegel, Daniela Rojas Castro, Hortense Fayé-Ketté, Amadou Koné, Souba Diandé, Claver A Dagnra, Laetitia Serrano, Fodié Diallo, Ephrem Mensah, Ter Tiero E Dah, Camille Anoma, Bea Vuylsteke, Bruno Spire, Christian Laurent, Issifou Yaya, Sayouba Ouedraogo, Bruno Granouillac, Gwenvael Le Guicher, Laetitia Serrano, Martine Peeters, Clotilde Couderc, Bruno Spire, Luis Sagaon-Teyssier, Marion Mora, Gwenaëlle Maradan, Michel Bourrelly, Mohamed Mimi, Cyril Berenger, Sylvie Boyer, Daniela Rojas Castro, Lucas Riegel, Paméla Palvadeau, Bea Vuylsteke, Irith De Baetselier, Thijs Reyniers, Bintou Dembélé Keita, Fodié Diallo, Alou Coulibaly, Alassane Kader Maïga, Drissa Camara, Mahamadou Diarra, Aly Ouologuem, Naboh Sangaré, Abdoul Aziz Keita, Oumar Cissé, Fodé Traoré, Bréhima Abdrahamane Ouary, Ibrahima Kanta, Camille Anoma, Jean-Baptiste Malan, Rachelle Kotchi, Niamkey Thomas Aka, Kpassou Julien Lokrou, Noufo Hamed Coulibaly, Ekissi Jean Armel Koffi, Dibi Frédéric N'guessan, Stéphane-Alain Babo Yoro, Adama Cissé, Ter Tiero Elias Dah, Issa Traoré, Camille Rajaonarivelo, Fayçal Rodrique Ouedraogo, Joseph Ouedraogo, Christian Coulibaly, Mamadou Ouedraogo, Ousseni Ilboudo, Abdoulazziz Traoré, Honoré Comsiambo, Ephrem Mensah, Mawuényégan Kouamivi Agboyibor, Anani Attisso, Anouwarsadat Kokouba, Aléda Mawuli Badjassim, Kouakou Kokouvi Selom Agbomadji, Messan Attiogbe, Kossi Jeff Yaka, Agbégnigan Lorette Ekon, Julien Bimba, Claver Anoumou Dagnra, Kokou Dominique Tegueni
Journal: The Lancet HIV (2021)
Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation
Authors: Nisha Padmanabhan, Huang Kie Kyon, Arnoud Boot, Kevin Lim, Supriya Srivastava, Shuwen Chen, Zhiyuan Wu, Hyung-Ok Lee, Vineeth T. Mukundan, Charlene Chan, Yarn Kit Chan, Ong Xuewen, Jason J. Pitt, Zul Fazreen Adam Isa, Manjie Xing, Ming Hui Lee, Angie Lay Keng Tan, Shamaine Ho Wei Ting, Micah A. Luftig, Dennis Kappei, Warren D. Kruger, Jinsong Bian, Ying Swan Ho, Ming Teh, Steve George Rozen, Patrick Tan
Journal: Genome biology (2021)

Abstract Background CIMP (CpG island methylator phenotype) is an epigenetic molecular subtype, observed in multiple malignancies and associated with the epigenetic silencing of tumor suppressors. Currently, for most cancers including gastric cancer (GC), mechanisms underlying CIMP remain poorly understood. We sought to discover molecular contributors to CIMP in GC, by performing global DNA methylation, gene expression, and proteomics profiling across 14 gastric cell lines, followed by similar integrative analysis in 50 GC cell lines and 467 primary GCs. Results We identify the cystathionine beta-synthase enzyme (CBS) as a highly recurrent target of epigenetic silencing in CIMP GC. Likewise, we show that CBS epimutations are significantly associated with CIMP in various other cancers, occurring even in premalignant gastroesophageal conditions and longitudinally linked to clinical persistence. Of note, CRISPR deletion of CBS in normal gastric epithelial cells induces widespread DNA methylation changes that overlap with primary GC CIMP patterns. Reflecting its metabolic role as a gatekeeper interlinking the methionine and homocysteine cycles, CBS loss in vitro also causes reductions in the anti-inflammatory gasotransmitter hydrogen sulfide (H 2 S), with concomitant increase in NF-κB activity. In a murine genetic model of CBS deficiency, preliminary data indicate upregulated immune-mediated transcriptional signatures in the stomach. Conclusions Our results implicate CBS as a bi-faceted modifier of aberrant DNA methylation and inflammation in GC and highlights H 2 S donors as a potential new therapy for CBS -silenced lesions.
AB0837 SERUM YKL-40 LEVELS IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS: RELATION TO DISEASE ACTIVITY AND JOINT DESTRUCTION
Authors: E. Aleksandrova, A. Novikov, E. Luchikhina, D. Karateev, G. Lukina
Journal: Annals of the Rheumatic Diseases (2021)

Background: YKL-40 (chitinase-3-like 1 protein, human cartilage glycoprotein 39) is one of the major proteins secreted locally in the arthritic joint by activated macrophages, chondrocytes, synoviocytes and neutrophils, YKL-40 an important marker for inflammation, cartilage remodelling and synovial hyperplasia is recognized as a possible auto-antigen in rheumatoid arthritis (RA). Objectives: The aims of the study were to determine the serum level of YKL-40 in early RA and investigate his relationship with biomarkers of disease activity and joint destruction. Methods: We studied 22 patients with early RA (ACR/EULAR 2010 classification criteria); 4 males, 18 females; median and interquartile range (25th—75th percentile) of age 55,0 (43,0-64,0) years, disease duration 7,0 (5,0-11,0) months, DAS28 4,9 (4,3-5,8); 86% IgM rheumatoid factor (IgM RF) +; 91% anti-cyclic citrullinated peptide antibody (anti-CCP) +. All patients were treated with methotrexate (MTX). Three (14 %) patients received low oral doses of steroids and intra-articular injections. The control group included 22 healthy donors (HC). Radiographs were scored according to the van der Heijde-modified Sharp score. YKL-40, matrix metalloproteinase-3 (MMP-3), anti-CCP were detected using commercially available enzyme-linked immunosorbent assays (ELISA). The serum levels of IgM RF, C-reactive protein (CRP), serum amyloid A (SAA) were measured by immunonephelometry. Results: RA patients had significantly higher serum level of YKL-40 than HC (92,1; 68,5-153,1 pg/ml vs 54,0; 41,7-83,2 pg/ml, p&lt;0.01). Serum YKL-40 concentration was positively correlated with DAS 28 (r=0,5; p&lt;0,05), erythrocyte sedimentation rate (ESR) (r=0,5; p&lt;0,05), CRP (r=0,8; p&lt;0,05), SAA (r=0,6; p&lt;0,05) and MMP-3 (r = 0,6; p&lt;0,05). We found no relationship between the level of YKL-40 and articular radiographic changes. Conclusion: Elevated serum concentration of YKL-40 in early RA is associated with clinical and laboratory indicators of disease inflammatory activity and increased level of MMP-3 - an immunological marker of joint destruction. Disclosure of Interests: Elena Aleksandrova: None declared, Alexander Novikov: None declared, Elena Luchikhina Speakers bureau: Abbvie, Roche, Pfizer, Biocad, MSD, Sanofi, Johnson &amp; Johnson, Glaxo, UCB, Celgene, Novartis, Consultant of: Abbvie, Biocad, Sanofi, Celgene, Dmitriy Karateev Speakers bureau: Abbvie, Roche, Pfizer, Biocad, MSD, Sanofi, Johnson &amp; Johnson, Glaxo, UCB, Celgene, Novartis, Lilly, Bayer, Paid instructor for: Abbvie, Pfizer, Biocad, Sanofi, Novartis, Lilly, Galina Lukina Speakers bureau: Abbvie, Roche, Pfizer, Biocad, MSD, Sanofi, Johnson &amp; Johnson, Glaxo, UCB, Celgene, Novartis, Paid instructor for: Abbvie, Biocad, Sanofi, Celgene
Effect of Recombinant Human Parathyroid Hormone (1-84) on Resolution of Active Charcot Neuro-osteoarthropathy in Diabetes: A Randomized, Double-Blind, Placebo-Controlled Study
Authors: Nina L. Petrova, Nicholas K. Donaldson, Maureen Bates, Wegin Tang, Timothy Jemmott, Victoria Morris, Tracy Dew, Lisa Meacock, David A. Elias, Cajetan F. Moniz, Michael E. Edmonds
Journal: Diabetes Care (2021)

Fractures in Charcot neuro-osteoarthropathy (CN) often fail to heal despite prolonged immobilization with below-knee casting. The aim of the study was to assess the efficacy of recombinant human parathyroid hormone (PTH) in reducing time to resolution of CN and healing of fractures.People with diabetes and acute (active) Charcot foot were randomized (double-blind) to either full-length PTH (1-84) or placebo therapy, both in addition to below-knee casting and calcium and vitamin D3 supplementation. The primary outcome was resolution of CN, defined as a skin foot temperature difference >2°C at two consecutive monthly visits.Median time to resolution was 5 months (95% CI 4, 12) in intervention and 6 months (95% CI 2, 9) in control. On univariate mixed Cox and logistic regression, there was no significant difference in time to resolution between the groups (P = 0.64) or in the likelihood of resolution (P = 0.66). The hazard ratio of resolution was 0.84 (95% CI 0.41, 1.74; P = 0.64), and the odds ratio of resolution by 12 months was 0.80 (95% CI 0.3, 2.13; P = 0.66) (intervention vs. control). On linear regression analysis, there were no significant differences in the effect of treatment on fracture scores quantitated on MRI scans (coefficient 0.13 [95% CI -0.62, 0.88]; P = 0.73) and on foot and ankle X-rays (coefficient 0.30 [95% CI -0.03, 0.63]; P = 0.07).This double-blind placebo-controlled trial did not reduce time to resolution or enhance fracture healing of CN. There was no added benefit of daily intervention with PTH (1-84) to below-knee casting in achieving earlier resolution of CN.
US drug regulator issues its first ever non-compliance notice for not posting trial results
Authors: Janice Hopkins Tanne
Journal: BMJ (2021)

The US drug regulator is reviewing a drug company’s reporting of a study on www.clinicaltrials.gov, after it issued its first ever notice of non-compliance last month when the company failed to file the study’s results on time.

The Food and Drug Administration gave Acceleron Pharma, of Cambridge, Massachusetts, 30 days to comply with the notice and warned that failure could mean a fine of $10 000 (£7045; €8200) a day and/or criminal penalties.12

Clinicaltrials.gov was established in 2000 as a public repository of clinical trials sponsored by academic institutions, hospitals, private companies, government research organisations, and individual researchers to make research widely available to doctors and the public and to prevent data about drugs from being hidden. There is a legal requirement for …
AB0603 THE NEW POSSIBILITIES OF USING CHONDROITIN SULFATE IN PATIENTS WITH KNEE OSTEOARTHRITIS
Authors: E. Sharapova, N. Kashevarova, E. Taskina, D. Kusevich, L. Alekseeva, A. Lila
Journal: Annals of the Rheumatic Diseases (2021)

Background: Administration of Chondroitin Sulfate for treatment of osteoarthritis included treatment types include systemic and parenteral therapies. The benefits of local therapies between difference route is ambivalent. Objectives: To evaluate effectiveness and safety of Chondroitin Sulfate (CS) by intramuscular and concomitant (intramuscular and intraarticular) route of administration in patients with knee osteoarthritis (OA). Methods: In total 150 patients with knee OA according by ACR criteria and with radiological stages 2 and 3 according to Kellgren-Lawrence were enrolled. Patients were divided by 2 groups: 75 patients (R) received course of 25 intramuscular injection every other day: at the first 3 injection’s in dose 100 mg, and in continue in dose 200 mg, 75 patients in 2nd group (N) received 5 intra-articular injections in target knee in dose 200 mg once per 3 days, in continue 16 intramuscular injections every other day in dose 200 mg. All patients received NSAID - meloxicam in stable dose 15 mg per day. All patients were checked by WOMAC, pain by visual analog scale (VAS), McGiIl Pain Questionnaire (MPQ). At the baseline, standard clinical examination for all patients were blood tests, urine test, coagulation panel and ECG. Results: After comparing of two groups by the end of course the intensity of pain by VAS was significantly greater in R group (21,88±13,24 vs 16,81±13,49; р&lt;0,0001). There were no significant differences between groups in improvement of WOMAC, WOMAC subscales and MPQ from baseline. Serious adverse events (AE) were absent. 11 AE’s were detected 3,3% (5/150), but in 100% of cases AE’s were resolved by the end of course. Conclusion: CS is effective decreased intensity of pain and stiffness, improved functional ability of joints both intramuscular and concomitant route of administration. However, significantly greater results at pain intensity by VAS shows combination: pain intensity by the end of course was significantly lower in group with concomitant intramuscular and intra-articular injections. Probably, it was associated with faster resolution of synovitis by intraarticular route of administration, that leads to choose this route for patients with comorbidity. Disclosure of Interests: None declared.
Use of Tofacitinib, 2%, Ointment for Periorbital Discoid Lupus Erythematosus
Authors: Daniel R. Mazori, Michelle S. Min, Bina Kassamali, Lars Brichta, Joseph F. Merola, Ruth Ann Vleugels, Avery H. LaChance
Journal: JAMA Dermatology (2021)

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Fungal keratitis at a tertiary eye care in Northern Thailand: Etiology and prognostic factors for treatment outcomes
Authors: Napaporn Tananuvat, Phit Upaphong, Chulaluck Tangmonkongvoragul, Muanploy Niparugs, Winai Chaidaroon, Monsicha Pongpom
Journal: Journal of Infection (2021)
N6-methyladenosine RNA modification regulates strawberry fruit ripening in an ABA-dependent manner
Authors: Leilei Zhou, Renkun Tang, Xiaojing Li, Shiping Tian, Bingbing Li, Guozheng Qin
Journal: Genome biology (2021)

Abstract Background Epigenetic mark such as DNA methylation plays pivotal roles in regulating ripening of both climacteric and non-climacteric fruits. However, it remains unclear whether mRNA m 6 A methylation, which has been shown to regulate ripening of the tomato, a typical climacteric fruit, is functionally conserved for ripening control among different types of fruits. Results Here we show that m 6 A methylation displays a dramatic change at ripening onset of strawberry, a classical non-climacteric fruit. The m 6 A modification in coding sequence (CDS) regions appears to be ripening-specific and tends to stabilize the mRNAs, whereas m 6 A around the stop codons and within the 3′ untranslated regions is generally negatively correlated with the abundance of associated mRNAs. We identified thousands of transcripts with m 6 A hypermethylation in the CDS regions, including those of NCED5 , ABAR , and AREB1 in the abscisic acid (ABA) biosynthesis and signaling pathway. We demonstrate that the methyltransferases MTA and MTB are indispensable for normal ripening of strawberry fruit, and MTA-mediated m 6 A modification promotes mRNA stability of NCED5 and AREB1 , while facilitating translation of ABAR . Conclusion Our findings uncover that m 6 A methylation regulates ripening of the non-climacteric strawberry fruit by targeting the ABA pathway, which is distinct from that in the climacteric tomato fruit.