tbuckley/cabot-search huggingface dataset:
Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy
Authors: Muhammad Riaz, Jinkyu Park, Lorenzo R. Sewanan, Yongming Ren, Jonas Schwan, Subhash K. Das, Pawel T. Pomianowski, Yan Huang, Matthew W. Ellis, Jiesi Luo, Juli Liu, Loujin Song, I-Ping Chen, Caihong Qiu, Masayuki Yazawa, George Tellides, John Hwa, Lawrence H. Young, Lei Yang, Charles C. Marboe, Daniel L. Jacoby, Stuart G. Campbell, Yibing Qyang
Journal: Circulation (2022)

Background: Familial hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. HCM manifestations include left ventricular hypertrophy and heart failure, arrythmias, and sudden cardiac death. How dysregulated sarcomeric force production is sensed and leads to pathological remodeling remains poorly understood in HCM, thereby inhibiting the efficient development of new therapeutics. Methods: Our discovery was based on insights from a severe phenotype of an individual with HCM and a second genetic alteration in a sarcomeric mechanosensing protein. We derived cardiomyocytes from patient-specific induced pluripotent stem cells and developed robust engineered heart tissues by seeding induced pluripotent stem cell–derived cardiomyocytes into a laser-cut scaffold possessing native cardiac fiber alignment to study human cardiac mechanobiology at both the cellular and tissue levels. Coupled with computational modeling for muscle contraction and rescue of disease phenotype by gene editing and pharmacological interventions, we have identified a new mechanotransduction pathway in HCM, shown to be essential in modulating the phenotypic expression of HCM in 5 families bearing distinct sarcomeric mutations. Results: Enhanced actomyosin crossbridge formation caused by sarcomeric mutations in cardiac myosin heavy chain ( MYH7 ) led to increased force generation, which, when coupled with slower twitch relaxation, destabilized the MLP (muscle LIM protein) stretch-sensing complex at the Z-disc. Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin–nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy. We demonstrate that the common muscle LIM protein–W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation. By mitigating enhanced actomyosin crossbridge formation through either genetic or pharmacological means, we alleviated stress at the Z-disc, preventing the development of hypertrophy associated with sarcomeric mutations. Conclusions: Our studies have uncovered a novel biomechanical mechanism through which dysregulated sarcomeric force production is sensed and leads to pathological signaling, remodeling, and hypertrophic responses. Together, these establish the foundation for developing innovative mechanism-based treatments for HCM that stabilize the Z-disc MLP-mechanosensory complex.
Rapid regression of uremic calcinosis
Authors: Tomasz Hołub, Marta Jagodzińska, Agnieszka Makówka, Kamila Kędzierska, Michał Nowicki
Journal: Kidney International (2022)

A 28-year-old man with end-stage kidney disease from posterior urethral valve undergoing peritoneal dialysis for 3.5 years, presented with pain and swelling of both shoulders. Computed tomography revealed numerous massive calcifications in the subcutaneous tissue around both shoulder joints (Figure 1a). Severe pain and limited mobility led to the need for high doses of opioids. Serum calcium concentration was 2.46 mmol/l, parathyroid hormone 139.4 pmol/l, and phosphate 2.94 mmol/l. Uremic tumoral calcinosis was diagnosed, and cinacalcet hydrochloride 30 mg daily was started; peritoneal dialysis was replaced by hemodialysis. Parathyroid ultrasound revealed a 6-mm adenoma for which parathyroidectomy was performed. Three months later, there was a remarkable reduction in calcification (Figure 1b), accompanied by pain relief and improvement in joint mobility. Plasma parathyroid hormone and calcium normalized rapidly to 11.38 pmol/l and 2.16 mmol/l, respectively. Tumoral calcinosis can be from genetic, traumatic, or metabolic causes. The most common metabolic cause of tumoral calcinosis is chronic uremia. Uremic tumoral calcinosis most frequently affects large joints, such as the elbows, shoulders, hips, and knees. Uremic tumoral calcinosis is rare and has been particularly associated, albeit rarely, in patients on peritoneal dialysis. Treatment strategies that have been tried include switching to a low-calcium hemodialysis treatment, parathyroidectomy, noncalcium phosphate binders, and sodium thiosulfate. MN received consulting fees from Amicus, Sanofi, Astellas, Takeda, PSI CRO, and Swixx Biopharma; honoraria for lectures and presentations from Amicus, Takeda, Sanofi, AstraZeneca, Swixx Biopharma, Fresenius Kabi, and Amgen; and support for attending meetings and travel from Amicus, Sanofi, and Roche. TH received honoraria for presentations from Sanofi. All the other authors declared no competing interests.
In inpatients with COVID-19 who need supplemental oxygen, lenzilumab increased ventilation-free survival
Authors: Vincent J. Mariano, Eleftherios Mylonakis
Journal: Annals of Internal Medicine (2022)

Source Citation Temesgen Z, Burger CD, Baker J, et al. Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a phase 3, randomised, placebo-controlled trial. Lancet Respir Med. 2022;10:237-46. 34863332
Efficacy of the eHealth application Oncokompas, facilitating incurably ill cancer patients to self-manage their palliative care needs: A randomized controlled trial
Authors: Anouk S. Schuit, Karen Holtmaat, Birgit I. Lissenberg-Witte, Simone E.J. Eerenstein, Josée M. Zijlstra, Corien Eeltink, Annemarie Becker-Commissaris, Lia van Zuylen, Myra E. van Linde, C. Willemien Menke-van der Houven van Oordt, Dirkje W. Sommeijer, Nol Verbeek, Koop Bosscha, Rishi Nandoe Tewarie, Robert-Jan Sedee, Remco de Bree, Alexander de Graeff, Filip de Vos, Pim Cuijpers, Irma M. Verdonck-de Leeuw
Journal: The Lancet Regional Health - Europe (2022)

Many patients with incurable cancer have symptoms affecting their health-related quality of life. The eHealth application 'Oncokompas' supports patients to take an active role in managing their palliative care needs, to reduce symptoms and improve health-related quality of life (HRQOL). This randomized controlled trial was conducted to determine the efficacy of Oncokompas compared to care as usual among incurably ill cancer patients with a life expectancy of more than three months.Patients were recruited in six hospitals in the Netherlands. Eligible patients were randomly assigned to the intervention (direct access to Oncokompas) or the control group (access to Oncokompas after three months). The primary outcome measure was patient activation (i.e., patients' knowledge, skills and confidence for self-management). Secondary outcomes were general self-efficacy and HRQOL. Measures were assessed at baseline, two weeks after randomization, and three months after the baseline measurement. Linear mixed models were used to compare longitudinal changes between both groups from baseline to the three-month follow-up.In total, 219 patients were eligible of which 138 patients completed the baseline questionnaire (response rate 63%), and were randomized to the intervention (69) or control group (69). There were no significant differences between the intervention and control group over time in patient activation (estimated difference in change T0-T2; 1·8 (90% CI: -1·0 to 4·7)), neither in general self-efficacy and HRQOL. Of the patients in the intervention group who activated their account, 74% used Oncokompas as intended. The course of patient activation, general self-efficacy, and HRQOL was not significantly different between patients who used Oncokompas as intended versus those who did not.Among incurably ill cancer patients with a life expectancy of more than three months and recruited in the hospital setting, Oncokompas did not significantly improve patient activation, self-efficacy, or HRQOL.ZonMw, Netherlands Organization for Health Research and Development (844001105).
Glioblastoma Recurrence Versus Radiotherapy Injury
Authors: Haodan Dang, Jinming Zhang, Ruimin Wang, Jiajin Liu, Huaping Fu, Mu Lin, Baixuan Xu
Journal: Clinical Nuclear Medicine (2022)

To evaluate the diagnostic potential of decision-tree model of diffusion kurtosis imaging (DKI) and 11C-methionine (11C-MET) PET, for the differentiation of radiotherapy (RT) injury from glioblastoma recurrence.Eighty-six glioblastoma cases with suspected lesions after RT were retrospectively enrolled. Based on histopathology or follow-up, 48 patients were diagnosed with local glioblastoma recurrence, and 38 patients had RT injury between April 2014 and December 2019. All the patients underwent PET/MRI examinations. Multiple parameters were derived based on the ratio of tumor to normal control (TNR), including SUVmax and SUVmean, mean value of kurtosis and diffusivity (MK, MD) from DKI, and histogram parameters. The diagnostic models were established by decision trees. Receiver operating characteristic analysis was used for evaluating the diagnostic accuracy of each independent parameter and all the diagnostic models.The intercluster correlations of DKI, PET, and texture parameters were relatively weak, whereas the intracluster correlations were strong. Compared with models of DKI alone (sensitivity =1.00, specificity = 0.70, area under the curve [AUC] = 0.85) and PET alone (sensitivity = 0.83, specificity = 0.90, AUC = 0.89), the combined model demonstrated the best diagnostic accuracy (sensitivity = 1.00, specificity = 0.90, AUC = 0.95).Diffusion kurtosis imaging, 11C-MET PET, and histogram parameters provide complementary information about tissue. The decision-tree model combined with these parameters has the potential to further increase diagnostic accuracy for the discrimination between RT injury and glioblastoma recurrence over the standard Response Assessment in Neuro-Oncology criteria. 11C-MET PET/MRI may thus contribute to the management of glioblastoma patients with suspected lesions after RT.
KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming
Authors: Feifei Na, Xiangyu Pan, Jingyao Chen, Xuelan Chen, Manli Wang, Pengliang Chi, Liting You, Lanxin Zhang, Ailing Zhong, Lei Zhao, Siqi Dai, Mengsha Zhang, Yiyun Wang, Bo Wang, Jianan Zheng, Yuying Wang, Jing Xu, Jian Wang, Baohong Wu, Mei Chen, Hongyu Liu, Jianxin Xue, Meijuan Huang, Youling Gong, Jiang Zhu, Lin Zhou, Yan Zhang, Min Yu, Panwen Tian, Mingyu Fan, Zhenghao Lu, Zhihong Xue, Yinglan Zhao, Hanshuo Yang, Chengjian Zhao, Yuan Wang, Junhong Han, Shengyong Yang, Dan Xie, Lu Chen, Qian Zhong, Musheng Zeng, Scott W. Lowe, You Lu, Yu Liu, Yuquan Wei, Chong Chen
Journal: Nature Cancer (2022)
Open Heart
Authors: Zoe Onion
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Recombinant von Willebrand factor prophylaxis in patients with severe von Willebrand disease: phase 3 study results
Authors: Frank W. G. Leebeek, Flora Peyvandi, Miguel Escobar, Andreas Tiede, Giancarlo Castaman, Michael Wang, Tung Wynn, Jovanna Baptista, Yi Wang, Jingmei Zhang, Björn Mellgård, Gülden Özen
Journal: Blood (2022)

International guidelines conditionally recommend long-term prophylaxis in patients with von Willebrand disease (VWD) and severe and frequent bleeding. As recombinant von Willebrand factor (rVWF; vonicog alfa) may reduce the frequency of treated spontaneous bleeding events (BEs), we investigated the efficacy and safety of rVWF prophylaxis in adults with severe VWD. Patients with BEs requiring VWF therapy in the past year (on-demand VWF therapy [prior on-demand group] or plasma-derived VWF prophylaxis [pdVWF; switch group]) were enrolled in a prospective, open-label, nonrandomized, phase 3 study. The planned duration of rVWF prophylaxis was 12 months; starting rVWF dose was 50 ± 10 VWF: ristocetin cofactor (VWF:RCo) IU/kg twice weekly (prior on-demand group) or based on prior pdVWF weekly dose/dosing frequency (switch group). The primary endpoint was annualized bleeding rate (ABR) of treated spontaneous BEs (sABR) during rVWF prophylaxis. Over the 12-month study period, treated sABR decreased by 91.5% on-study vs historical sABR in 13 patients in the prior on-demand group, and by 45.0% in 10 patients in the switch group (model-based analysis ratio, 0.085; 95% confidence interval [CI], 0.021-0.346 and 0.550; 95% CI, 0.086-3.523, respectively). No treated spontaneous BEs were recorded in 84.6% (11/13) and 70.0% (7/10) of patients, respectively. The safety profile of rVWF was consistent with the previously established profile, with no new adverse drug reactions identified. Findings suggest that rVWF prophylaxis can reduce treated spontaneous BEs in patients previously receiving on-demand VWF therapy and maintains at least the same level of hemostatic control in patients who switch from prophylaxis with pdVWF to rVWF, with a favorable safety profile. This trial was registered at www.clinicaltrials.gov (#NCT02973087) and www.clinicaltrialsregister.eu (#EudraCT 2016-001478-14).
Nivolumab Immunotherapy–Related Skin Reactions Detected on 18F-FDG PET/CT in Renal Cell Cancer
Authors: Thayumanavan T, Harish Goyal, Harmandeep Singh, Chandan K. Das, Aravind Sekar, Rajender Kumar
Journal: Clinical Nuclear Medicine (2022)

Nivolumab, a fully human immunoglobulin G4 anti-programmed cell death 1 antibody, provides a novel therapy option for patients with metastatic cancers. Immunotherapy agents have been associated with immune-related adverse events (irAEs), which may be detected on 18F-FDG PET/CT. Cutaneous toxicities are one of the most common irAEs in the form of maculopapular rash (eczema-like spongiotic dermatitis) and pruritus. These irAEs may lead to false-positive findings on PET/CT done during the treatment. One should be aware of the potential irAEs while interpreting PET/CT to avoid misinterpretation.
Neutralization and receptor use of infectious culture–derived rat hepacivirus as a model for HCV
Authors: Raphael Wolfisberg, Caroline E. Thorselius, Eduardo Salinas, Elizabeth Elrod, Sheetal Trivedi, Louise Nielsen, Ulrik Fahnøe, Amit Kapoor, Arash Grakoui, Charles M. Rice, Jens Bukh, Kenn Holmbeck, Troels K. H. Scheel
Journal: Hepatology (2022)

Abstract Background and Aims Lack of tractable immunocompetent animal models amenable to robust experimental challenge impedes vaccine efforts for HCV. Infection with rodent hepacivirus from Rattus norvegicus (RHV‐rn1) in rats shares HCV‐defining characteristics, including liver tropism, chronicity, and pathology. RHV in vitro cultivation would facilitate genetic studies on particle production, host factor interactions, and evaluation of antibody neutralization guiding HCV vaccine approaches. Approach and Results We report an infectious reverse genetic cell culture system for RHV‐rn1 using highly permissive rat hepatoma cells and adaptive mutations in the E2, NS4B, and NS5A viral proteins. Cell culture–derived RHV‐rn1 particles (RHVcc) share hallmark biophysical characteristics of HCV and are infectious in mice and rats. Culture adaptive mutations attenuated RHVcc in immunocompetent rats, and the mutations reverted following prolonged infection, but not in severe combined immunodeficiency (SCID) mice, suggesting that adaptive immune pressure is a primary driver of reversion. Accordingly, sera from RHVcc‐infected SCID mice or the early acute phase of immunocompetent mice and rats were infectious in culture. We further established an in vitro RHVcc neutralization assay, and observed neutralizing activity of rat sera specifically from the chronic phase of infection. Finally, we found that scavenger receptor class B type I promoted RHV‐rn1 entry in vitro and in vivo. Conclusions The RHV‐rn1 infectious cell culture system enables studies of humoral immune responses against hepacivirus infection. Moreover, recapitulation of the entire RHV‐rn1 infectious cycle in cell culture will facilitate reverse genetic studies and the exploration of tropism and virus–host interactions.
Body Size at Different Ages and Risk of 6 Cancers: A Mendelian Randomization and Prospective Cohort Study
Authors: Daniela Mariosa, Karl Smith-Byrne, Tom G Richardson, Pietro Ferrari, Marc J Gunter, Nikos Papadimitriou, Neil Murphy, Sofia Christakoudi, Konstantinos K Tsilidis, Elio Riboli, David Muller, Mark P Purdue, Stephen J Chanock, Rayjean J Hung, Christopher I Amos, Tracy A O’Mara, Pilar Amiano, Fabrizio Pasanisi, Miguel Rodriguez-Barranco, Vittorio Krogh, Anne Tjønneland, Jytte Halkjær, Aurora Perez-Cornago, María-Dolores Chirlaque, Guri Skeie, Charlotta Rylander, Kristin Benjaminsen Borch, Dagfinn Aune, Alicia K Heath, Heather A Ward, Matthias Schulze, Catalina Bonet, Elisabete Weiderpass, George Davey Smith, Paul Brennan, Mattias Johansson
Journal: JNCI Journal of the National Cancer Institute (2022)

It is unclear if body weight in early life affects cancer risk independently of adult body weight. To investigate this question for 6 obesity-related cancers, we performed univariable and multivariable analyses using 1) Mendelian randomization (MR) analysis and 2) longitudinal analyses in prospective cohorts. Both the MR and longitudinal analyses indicated that larger early life body size was associated with higher risk of endometrial (odds ratioMR = 1.61, 95% confidence interval = 1.23 to 2.11) and kidney (odds ratioMR = 1.40, 95% confidence interval = 1.09 to 1.80) cancer. These associations were attenuated after accounting for adult body size in both the MR and cohort analyses. Early life body mass index (BMI) was not consistently associated with the other investigated cancers. The lack of clear independent risk associations suggests that early life BMI influences endometrial and kidney cancer risk mainly through pathways that are common with adult BMI.
Effect of BTN162b2 and CoronaVac boosters on humoral and cellular immunity of individuals previously fully vaccinated with CoronaVac against SARS‐CoV‐2: A longitudinal study
Authors: Zeynep Ece Kuloğlu, Rojbin El, Gulen Guney‐Esken, Yeşim Tok, Zeynep Gülçe Talay, Tayfun Barlas, Mert Ahmet Kuskucu, Özgür Albayrak, Özlem Doğan, Serap Şimşek Yavuz, Kenan Midilli, Önder Ergönül, Füsun Can
Journal: Allergy (2022)

It is essential to know about immune response levels after booster doses of the two different types of vaccines, mRNA, and the inactivated, currently used against COVID-19. For this purpose, we aimed to determine the effects of BNT162b2 (BNT) and CoronaVac (CV) boosters on the humoral and cellular immunity of individuals who had two doses of CV vaccination.
Inhibition of the enzyme autotaxin reduces cortical excitability and ameliorates the outcome in stroke
Authors: Lynn Bitar, Timo Uphaus, Carine Thalman, Muthuraman Muthuraman, Luzia Gyr, Haichao Ji, Micaela Domingues, Heiko Endle, Sergiu Groppa, Falk Steffen, Nabin Koirala, Wei Fan, Laura Ibanez, Laura Heitsch, Carlos Cruchaga, Jin-Moo Lee, Florian Kloss, Stefan Bittner, Robert Nitsch, Frauke Zipp, Johannes Vogt
Journal: Science Translational Medicine (2022)

Stroke penumbra injury caused by excess glutamate is an important factor in determining stroke outcome; however, several therapeutic approaches aiming to rescue the penumbra have failed, likely due to unspecific targeting and persistent excitotoxicity, which continued far beyond the primary stroke event. Synaptic lipid signaling can modulate glutamatergic transmission via presynaptic lysophosphatidic acid (LPA) 2 receptors modulated by the LPA-synthesizing molecule autotaxin (ATX) present in astrocytic perisynaptic processes. Here, we detected long-lasting increases in brain ATX concentrations after experimental stroke. In humans, cerebrospinal fluid ATX concentration was increased up to 14 days after stroke. Using astrocyte-specific deletion and pharmacological inhibition of ATX at different time points after experimental stroke, we showed that inhibition of LPA-related cortical excitability improved stroke outcome. In transgenic mice and in individuals expressing a single-nucleotide polymorphism that increased LPA-related glutamatergic transmission, we found dysregulated synaptic LPA signaling and subsequent negative stroke outcome. Moreover, ATX inhibition in the animal model ameliorated stroke outcome, suggesting that this approach might have translational potential for improving the outcome after stroke.
Optical coherence tomography in coronary atherosclerosis assessment and intervention
Authors: Makoto Araki, Seung-Jung Park, Harold L. Dauerman, Shiro Uemura, Jung-Sun Kim, Carlo Di Mario, Thomas W. Johnson, Giulio Guagliumi, Adnan Kastrati, Michael Joner, Niels Ramsing Holm, Fernando Alfonso, William Wijns, Tom Adriaenssens, Holger Nef, Gilles Rioufol, Nicolas Amabile, Geraud Souteyrand, Nicolas Meneveau, Edouard Gerbaud, Maksymilian P. Opolski, Nieves Gonzalo, Guillermo J. Tearney, Brett Bouma, Aaron D. Aguirre, Gary S. Mintz, Gregg W. Stone, Christos V. Bourantas, Lorenz Räber, Sebastiano Gili, Kyoichi Mizuno, Shigeki Kimura, Toshiro Shinke, Myeong-Ki Hong, Yangsoo Jang, Jin Man Cho, Bryan P. Yan, Italo Porto, Giampaolo Niccoli, Rocco A. Montone, Vikas Thondapu, Michail I. Papafaklis, Lampros K. Michalis, Harmony Reynolds, Jacqueline Saw, Peter Libby, Giora Weisz, Mario Iannaccone, Tommaso Gori, Konstantinos Toutouzas, Taishi Yonetsu, Yoshiyasu Minami, Masamichi Takano, O. Christopher Raffel, Osamu Kurihara, Tsunenari Soeda, Tomoyo Sugiyama, Hyung Oh Kim, Tetsumin Lee, Takumi Higuma, Akihiro Nakajima, Erika Yamamoto, Krzysztof L. Bryniarski, Luca Di Vito, Rocco Vergallo, Francesco Fracassi, Michele Russo, Lena M. Seegers, Iris McNulty, Sangjoon Park, Marc Feldman, Javier Escaned, Francesco Prati, Eloisa Arbustini, Fausto J. Pinto, Ron Waksman, Hector M. Garcia-Garcia, Akiko Maehara, Ziad Ali, Aloke V. Finn, Renu Virmani, Annapoorna S. Kini, Joost Daemen, Teruyoshi Kume, Kiyoshi Hibi, Atsushi Tanaka, Takashi Akasaka, Takashi Kubo, Satoshi Yasuda, Kevin Croce, Juan F. Granada, Amir Lerman, Abhiram Prasad, Evelyn Regar, Yoshihiko Saito, Mullasari Ajit Sankardas, Vijayakumar Subban, Neil J. Weissman, Yundai Chen, Bo Yu, Stephen J. Nicholls, Peter Barlis, Nick E. J. West, Armin Arbab-Zadeh, Jong Chul Ye, Jouke Dijkstra, Hang Lee, Jagat Narula, Filippo Crea, Sunao Nakamura, Tsunekazu Kakuta, James Fujimoto, Valentin Fuster, Ik-Kyung Jang
Journal: Nature Reviews Cardiology (2022)