tbuckley/cabot-search huggingface dataset:
Neurodegenerative effect of DAPK1 after cerebral hypoxia-ischemia is associated with its post-transcriptional and signal transduction regulations: A systematic review and meta-analysis
Authors: Zeeshan Ahmad Khan, Dewan Md. Sumsuzzman, Jeonghyun Choi, Yonggeun Hong
Journal: Ageing Research Reviews (2022)

Cerebral hypoxia-ischemia (CHI) causes brain aging, neurological disorders, cognitive decline, motor function impairment, and mortality. Inhibiting death-associated protein kinase 1 (DAPK1) has shown therapeutic potential against CHI, but several reports contradict its protective function, mechanism of activation, and signal transduction. Here, we systematically reviewed the role and the activation mechanism of DAPK1, and quantitatively assess the efficacy of DAPK1 inhibition (DI) methods in neuroprotection, following a CHI in animal models. Embase and PubMed were searched for relevant studies. Overall, 13 studies met the inclusion criteria, and the SYRCLE Risk of bias tool (RoB) tool was used to assess RoB. StataSE 16 was used for meta-analysis and network meta-analysis (NMA). Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated to estimate the effect size. DI was associated with the reduction of brain infarct volume (BIV) [SMD = -1.70, 95% CI (-2.10, -1.30); p = 0.00], neurological score (N.S.), neuronal degeneration, with no change in the level of in cell death [SMD = -0.83, 95% CI (-2.00, 0.35); p = 0.17], indicating the protective role of DI against CHI. No differences were found in DAPK1 mRNA and protein levels [SMD = 0.50, 95% CI (-0.05, 1.04); p = 0.07] {single-study driven; upregulated after exclusion (p = 0.01, I2 = 36.43)}, whereas phospho-DAPK1 [SMD = -2.22, 95% CI (-3.69, -0.75); p = 0.00] was downregulated and phosphorylated myosin light chain [SMD = 3.37, 95% CI (2.51, 4.96); p = 0.00] was upregulated between CHI and sham groups. Furthermore, we performed NMA to understand the molecular level at which DI offers maximum protection against BIV. Post-transcriptional inhibition (PTI; SUCRA, 82.6%) and gene knockout showed best (KO; SUCRA, 81.3%), signal transduction inhibition (STI; SUCRA, 49.5%) offered 3rd best, while catalytic activity inhibition (CAI; SUCRA, 0.3%) exhibited the lowest reduction in BIV against CHI. The results demonstrate that DI has a neuroprotective effect against CHI and DAPK1 might be regulated at the post-transcriptional and post-translational levels after CHI. Inhibiting DAPK1 at the post-transcriptional level and blocking multiple signal transduction pathways of DAPK1 could lead to better functional recovery against CHI. AVAILABILITY OF DATA AND MATERIALS: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
PEARLS: A multicenter phase II/III trial of extended field radiotherapy for androgen-sensitive prostate cancer patients with PSMA‐avid pelvic and para-aortic lymph nodes at presentation.
Authors: Julia Murray, Clare Cruickshank, Thomas Bird, Philip Bell, John Braun, Dave Chuter, Reena Davda, Miguel Reis Ferreira, Clare Griffin, Nabil Hujairi, Alan Melcher, Elizabeth Miles, Olivia Naismith, Jan Rekowski, John Staffurth, Isabel Syndikus, Alison Tree, Anna Wilkins, Emma Hall
Journal: Journal of Clinical Oncology (2022)

TPS199 Background: Optimal management for lymph node (LN) positive prostate cancer has not yet been determined. With the emerging role of PSMA-PET/CT in diagnostic staging, identification of this disease status is increasing. The superior border for prostate nodal radiotherapy is variable across different centres. PEARLS (CRUK/19/016) aims to show that extending the radiotherapy field to cover the para-aortic LN (up to L1/L2 vertebral interspace) can improve outcomes for prostate cancer patients with PSMA-avid pelvic LN at presentation. The trial is registered: ISRCTN36344989. Methods: PEARLS is a multi‐stage randomised controlled trial. Men with histologically confirmed prostate cancer with PSMA‐avid nodal disease within the pelvis +/‐ para‐aortic region receiving androgen deprivation therapy +/‐ androgen receptor targeted therapy or docetaxel chemotherapy are eligible. Two cohorts defined by extent of LN disease determined by PSMA‐PET/CT will be recruited: cohort A (pelvic LN at or below the L4/L5 vertebral interspace) and cohort B (para-aortic LN below L1/L2 vertebral interspace). Patients are randomly allocated (1:1) to standard field (dependent on cohort) intensity modulated radiotherapy (IMRT) (control) or extended-field IMRT (experimental) in 20 fractions over 4 weeks. In the control group, cohort A will receive 60Gy to the prostate and 44Gy to the pelvis with an integrated boost of 51Gy to PSMA-avid LN and cohort B will receive 60Gy to the prostate only. In the experimental group, participants in both cohorts will receive 60Gy to the prostate and 44Gy to the pelvis and para‐aortic region with an integrated boost of 51Gy to involved LN. In phase II, the primary endpoint is lower gastrointestinal RTOG grade 2+ toxicity at week 18 from start of radiotherapy. Assuming acceptable toxicity in the first 75 participants receiving extended-field IMRT, the study will move to phase III where the primary endpoint is metastasis‐free survival. The trial aims to recruit 714 patients with pelvic LN to detect a hazard ratio of 0.62 in favour of extended-field IMRT and a further 179 patients with para‐aortic LN disease. The trial was launched in the UK on 25 June 2021. Phase II will be conducted in 20 NHS Trusts across the UK. Clinical trial information: ISRCTN36344989.
Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19
Authors: Keith Sacco, Riccardo Castagnoli, Svetlana Vakkilainen, Can Liu, Ottavia M. Delmonte, Cihan Oguz, Ian M. Kaplan, Sara Alehashemi, Peter D. Burbelo, Farzana Bhuyan, Adriana A. de Jesus, Kerry Dobbs, Lindsey B. Rosen, Aristine Cheng, Elana Shaw, Mikko S. Vakkilainen, Francesca Pala, Justin Lack, Yu Zhang, Danielle L. Fink, Vasileios Oikonomou, Andrew L. Snow, Clifton L. Dalgard, Jinguo Chen, Brian A. Sellers, Gina A. Montealegre Sanchez, Karyl Barron, Emma Rey-Jurado, Cecilia Vial, Maria Cecilia Poli, Amelia Licari, Daniela Montagna, Gian Luigi Marseglia, Francesco Licciardi, Ugo Ramenghi, Valentina Discepolo, Andrea Lo Vecchio, Alfredo Guarino, Eli M. Eisenstein, Luisa Imberti, Alessandra Sottini, Andrea Biondi, Sayonara Mató, Dana Gerstbacher, Meng Truong, Michael A. Stack, Mary Magliocco, Marita Bosticardo, Tomoki Kawai, Jeffrey J. Danielson, Tyler Hulett, Manor Askenazi, Shaohui Hu, Jason Barnett, Xi Cheng, Krishnaveni Kaladi, Vasudev Kuram, Joseph Mackey, Neha M. Bansal, Andrew J. Martins, Boaz Palterer, Helen Matthews, Uma Mudunuri, Marshall Nambiar, Andrew J. Oler, Andre Rastegar, Smilee Samuel, Conrad Shyu, Varsha Waingankar, Sarah Weber, Sandhya Xirasagar, Yazmin Espinosa, Camila Astudillo, Cecilia Piñera, Ricardo González, Maria De Filippo, Martina Votto, Lorenza Montagna, Jeffrey I. Cohen, Helen C. Su, Douglas B. Kuhns, Michail S. Lionakis, Thomas M. Snyder, Steven M. Holland, Raphaela Goldbach-Mansky, John S. Tsang, Luigi D. Notarangelo
Journal: Nature Medicine (2022)
Detection rate of <sup>18</sup>F-rhPSMA-7.3 PET in patients with suspected prostate cancer recurrence: Results from a phase 3, prospective, multicenter study (SPOTLIGHT)
Authors: David M. Schuster
Journal: Journal of Clinical Oncology (2022)

9 Background: 18 F-labeled prostate-specific membrane antigen (PSMA) positron emission tomography (PET) ligands offer a longer half-life and improved spatial resolution compared with 68 Ga-PSMA. Here, we report the detection rate (DR) of 18 F-rhPSMA-7.3, a novel high affinity theranostic PET ligand with potential for low bladder activity. Methods: SPOTLIGHT (NCT04186845) assessed the coprimary endpoints of patient level Correct Detection Rate (CDR - % of all patients scanned with ≥1 true positive lesion) and region level Positive Predictive Value (all PET positive regions combined) of 18 F-rhPSMA-7.3 using histopathology and/or conventional imaging as a composite Standard of Truth (SoT). These metrics were also evaluated in a subset of patients with a histopathology-only SoT. Prespecified statistical thresholds of at least 36.5% and 62.5% were set for CDR and PPV, respectively. Overall DR stratified by PSA was also documented. Men with prostate cancer recurrence underwent PET 50-70 minutes after IV administration of 296 MBq 18 F-rhPSMA-7.3. Image guided biopsies of PET lesions took place ≤60 days post-PET and any confirmatory imaging took place ≤90 days. Three blinded central readers evaluated the scans with majority read accepted as final interpretation. A separate Truth Panel established SoT for each patient. Results: The overall DR in the 389 men (median [range] PSA, 1.10 [0.03-134.6] ng/mL) who had an evaluable 18 F-rhPSMA-7.3 scan is 83% by majority read (See Table). In the 366 men (median [range] PSA, 1.27 [0.03-134.6] ng/mL) with a composite SoT, the patient level CDR is 56.8% (95% CI, 51.6-62.0), meeting the prespecified threshold. The region level PPV is 59.7% (54.7-64.7), not meeting the prespecified threshold. In the subset of patients with a histopathology-only SoT, the patient level CDR and region level PPV are higher at 81.2% (69.9-89.6) and 71.6% (62.5-80.7), respectively. Both of these values would have met the prespecified thresholds. Conclusions: 18 F-rhPSMA-7.3 has a clinically meaningful CDR that meets the prespecified threshold. While the region level PPV does not meet the prespecified threshold, the data in patients with a composite SoT are limited by the high proportion of prostate/bed scans (92%) that relied on conventional imaging, a suboptimal SoT. For the subset of patients with the more robust histopathology SoT for at least one region per patient, a high PPV is seen and the lower bound of the 95% CI would have exceeded the prespecified threshold. Together, these data support the clinical utility of 18 F-rhPSMA-7.3 PET in men with recurrent prostate cancer across a wide PSA range. Clinical trial information: NCT04186845. [Table: see text]
Honing the treatment of early breast cancer
Authors: J. Henahan
Journal: JAMA (1984)

Most women with early breast cancer who undergo conservative surgery followed by radiation therapy can expect the same five- to ten-year survival rates as those women who undergo radical mastectomy, along with excellent cosmetic results, according to the findings of several large retrospective and prospective clinical trials detailed at the Sixth Annual Bristol-Myers Symposium on Cancer Research in Venice. Data are also emerging on clinical factors that may predict a poor response to such treatment in some women with early breast cancer. Evaluating the results of a series of retrospective studies carried out in Europe, involving a total of 2,600 women with early infiltrating carcinomas of the breast, Robert Calle, MD, Institut Curie, Paris, reported that the five-year survival rate ranged from 62% to 80%. Although protocols varied somewhat from center to center, treatment generally involved removal of the tumor bulk with several forms of limited surgery (lumpectomy, wedge resection,
Train at home, but not alone: a randomised controlled multicentre trial assessing the effects of live-streamed tele-exercise during COVID-19-related lockdowns
Authors: Jan Wilke, Lisa Mohr, Gustavo Yuki, Adelle Kemlall Bhundoo, David Jiménez-Pavón, Fernando Laiño, Niamh Murphy, Bernhard Novak, Stefano Nuccio, Sonia Ortega-Gómez, Julian David Pillay, Falk Richter, Lorenzo Rum, Celso Sanchez-Ramírez, David Url, Lutz Vogt, Luiz Hespanhol
Journal: British Journal of Sports Medicine (2022)

Public life restrictions associated with the COVID-19 pandemic caused reductions in physical activity (PA) and decreases in mental and somatic health. Considering the interplay between these factors, we investigated the effects of digital home exercise (DHE) during government-enforced lockdowns.A multicentre randomised controlled trial was performed allocating healthy individuals from nine countries (N=763; 523 female) to a DHE or an inactive control group. During the 4-week main intervention, DHE members engaged in live-streamed multicomponent home exercise. Subsequently, both groups had access to prerecorded workouts for an additional 4 weeks. Outcomes, assessed weekly, included PA level (Nordic Physical Activity Questionnaire-Short), anxiety (Generalized Anxiety Disorder Scale-7), mental well-being (WHO-5 Questionnaire), sleep quality (Medical Outcome Study Sleep Scale), pain/disability (Chronic Pain Grade Scale) and exercise motivation (Self-Concordance Scale). Mixed models were used for analysis.Live-streamed DHE consistently increased moderate PA (eg, week 1: 1.65 times more minutes per week, 95% CI 1.40 to 1.94) and vigorous PA (eg, week 1: 1.31 times more minutes per week, 95% CI 1.08 to 1.61), although the effects decreased over time. In addition, exercise motivation, sleep quality and anxiety were slightly improved for DHE in the 4-week live streaming period. The same applied to mental well-being (mean difference at week 4: +0.99, 95% CI 0.13 to 1.86), but an inverted trend was observed after live streaming was substituted by prerecorded exercise.Live-streamed DHE represents an efficacious method to enhance PA and selected markers of health during pandemic-related public life restrictions. However, research on implementation is warranted to reduce dropout rates.DRKS00021273.
Evaluation of Unreimbursed Medicaid Costs Among Nonprofit and For-Profit US Hospitals
Authors: Ge Bai, Hossein Zare, David A. Hyman
Journal: JAMA Network Open (2022)

In 2019, the 3446 US private hospitals in our data set incurred $20.59 billion in unreimbursed Medicaid costs, representing 2.52% of their total expenses.Nevada hospitals had the highest weighted mean unreimbursed Medicaid cost to expense ratio (7.74%), whereas hospitals in Maryland (0.02%), Utah (0.07%), and Alabama (0.14%) had the lowest ratios (Table ).In 23 of the 45 states (51.1%) in which both nonprofit and for-profit hospitals operated, for-profit hospitals had higher unreimbursed Medicaid cost to expense ratios than nonprofit hospitals (Figure).
Diagnostic role of internal mammary lymph node involvement in tuberculous pleurisy: a multicenter study
Authors: G. Levi, C. Rocchetti, F. Mei, G.M. Stella, S. Lettieri, F. Lococo, F. Taccari, C. Seguiti, M. Fantoni, F. Natali, P. Candoli, C. Bortolotto, V. Pinelli, M. Mondoni, P. Carlucci, A. Fabbri, M Trezzi, L. Vannucchi, M. Bonifazi, F. Porcarelli, S. Gasparini, G. Sica, T. Valente, D. Biondini, M. Damin, V. Liani, M. Tamburrini, C. Sorino, F. Mezzasalma, M.U. Scaramozzino, L. Pini, M. Bezzi, G.P. Marchetti
Journal: Pulmonology (2022)

Diagnosis of tuberculous pleurisy (TP) may be challenging and it often requires pleural biopsy. A tool able to increase pre-test probability of TP may be helpful to guide diagnostic work-up and enlargement of internal mammary lymph node (IMLN) has been suggested to play a potential role. The aim of the present investigation was to assess role of IMLN involvement in TP in a multi-centric case-control study, by comparing its prevalence and test performance to those observed in patients with infectious, non-tuberculous pleurisy (NTIP), and in controls free from respiratory diseases (CP). A total of 419 patients, from 14 Pulmonology Units across Italy were enrolled (127 patients affected by TP, 163 affected by NTIP and 129 CP). Prevalence, accuracy and predictive values of ipsilateral IMLN involvement between cases and control groups were assessed, as well as concordance between chest computed tomography (CT scan) and thoracic ultrasound (TUS) measurements. The prevalence of ipsilateral IMLN involvement in TP was significantly higher than that observed in NTIP and CP groups (respectively 77.2%, 39.3% and 14.7%). Results on test performance, stratified by age, revealed a high positive predictive value in patients aged ≤50 years, while a high negative predictive value in patients aged >50 years. The comparison between CT scan and ultrasound showed moderate agreement (Kappa=0.502). Evaluation of IMLN involvement plays a relevant role in assessing the pre-test probability of TP. Considering the increasing global prevalence of mycobacterial infections, a tool able to guide diagnostic work-up of suspected TP is crucial, especially where local sources are limited.
Influenza
Authors: J. Pesek
Journal: BMJ (1963)

5-6-5) 2k 24k 48k IiI71 96h4g 4 48 I2 I6 4h2h14 721 I6 41 Patient Before therapy -34 <0-75 60-0 30-0 15-0 1-6 4 days after "atoss- therapy".
Public health problems in the Olympic Games setting
Authors: C. L. Thomas
Journal: JAMA (1968)

At dusk on Oct 11, 1968, a flame brought from Greece will be placed on the Temple at Quetzalcoatl in the city of Teotihuacan, 25 miles north of Mexico City. The XIX Olympiad will begin the next day and continue through Oct 27. Following the placement of the Olympic torch on the temple, there will be a giant ballet portraying the ancient Aztec legend that the periodic rebirth of new fire conveys the promise of the gods of continued life for mankind. Because both the XIX Olympiad and the cultural Olympiad are to be held in Mexico this year, it is estimated that at least 200,000 tourists will visit our neighboring country in the month of October. You and your patients may ask if there are special medically related problems to be encountered in Mexico. If problems are anticipated, then they may be either prevented or adequately cared for. Those
Molecular and immune landscape of <i>FH</i>-mutated kidney cancer.
Authors: Bayan A Al-Share, Sharon Wu, Abdurahman Alloghbi, Samer Alkassis, Anthony Guastella, Anthony Helmstetter, Chadi Nabhan, W. Michael Korn, Bassel Nazha, Pedro C. Barata, Charles J. Ryan, Rana R. McKay, Elisabeth I. Heath
Journal: Journal of Clinical Oncology (2022)

382 Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by inactivating germline mutations in fumarate hydratase ( FH), predisposing individuals to development of certain cancers. Sporadic FH mutations have been described in different types of cancers, including kidney cancers, but the implications of somatic mutations are not well described. Here, we characterize the molecular landscape of kidney tumors with FH mutations. Methods: Tumors were analyzed using next generation sequencing of DNA (NextSeq, 592 genes and NovaSeq, WES) and RNA (NovaSeq). Immune cell fraction was estimated by immune deconvolution (Quantiseq). Significance was determined by chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons (q-value &lt;0.05). Results: Of 1956 kidney tumors, 31 had somatic pathogenic or likely pathogenic (P+LP; 1.58%) and 21 had variant of unknown significance (VUS; 1.07%) mutations in FH. Among the most commonly co-mutated genes, VHL (29.03% vs 38.1% vs 55.2%) and PBRM1 (9.68% vs 20% vs 29.8%) were less frequently mutated in P+LP compared to VUS and WT tumors; while NF2 (22.6% vs 5% vs 5.65%) was more frequently mutated in P+LP tumors compared to the others. In P+LP tumors, the HIPPO pathway (22.6% vs 4.76% vs 5.62%) was more frequently altered while the chromatin remodeling pathway (25.8% vs 28.6% vs 51.1%) was less frequently altered compared to VUS or WT tumors. P+LP tumors showed decreased NK cell infiltration (q=0.01) compared to VUS and WT tumors. Additionally, there was a trend towards increased CD8+ T cells and CTLA4 and PDCD1 expression in P+LP tumors compared to VUS but not WT tumors. Of the 1,956 kidney tumors, 315 were of clear cell renal cell carcinoma (ccRCC) histology. P+LP (n=4) ccRCC tumors showed a trend towards higher expression of immune checkpoint genes CTLA4 and IDO1 compared to VUS tumors (n=5). VHL expression was higher in P+LP ccRCC compared to VUS ccRCC tumors. P+LP ccRCC tumors showed a trend toward increased CD4+ (2.59% vs 0%) and CD8+ (2.14% vs 0%) T cells as well as T cell inflammation (25% vs 0%) and median Interferon score compared to VUS ccRCC tumors. Conclusions: P+LP FH mutated kidney tumors may have a different mutational and immune landscape than VUS FH mutated and WT tumors. Despite the small sample size, our study highlights potential therapeutic implications that will require further study.[Table: see text]
Oral contraceptives.
Authors: G. A. Holbrook
Journal: BMJ (1967)

ContraceptivesSIR,-At a time when the Dunlop Committte on Safety of Drugs has just reported on the contraceptive pill and has, albeit with reservations, put a " safe " level on it, I for one am feeling more and more uneasy about prescribing it.The excellent paper by Drs.
GSK-3β Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation
Authors: Marisa J. Stachowski-Doll, Maria Papadaki, Thomas G. Martin, Weikang Ma, Henry M. Gong, Stephanie Shao, Shi Shen, Nitha Aima Muntu, Mohit Kumar, Edith Perez, Jody L. Martin, Christine S. Moravec, Sakthivel Sadayappan, Stuart G. Campbell, Thomas Irving, Jonathan A. Kirk
Journal: Circulation Research (2022)

Altered kinase localization is gaining appreciation as a mechanism of cardiovascular disease. Previous work suggests GSK-3β (glycogen synthase kinase 3β) localizes to and regulates contractile function of the myofilament. We aimed to discover GSK-3β's in vivo role in regulating myofilament function, the mechanisms involved, and the translational relevance.
Topical corticosteroids.
Journal: BMJ (1969)

Breast to levels of moderate toxicity.There is no evidence that clinical benefit from cytotoxic agents in breast cancer runs parallel to the degree of the toxic side-effects. Male Breast CancerSurgical castration is the most effective endocrine method of achieving tumour regression in male breast cancer.Sub- capsular orchidectormy may be more acceptable psychologically than total orchidectomy, but enucleation of the testis must be complete to be effective.Radiation castration is not feasible in the male.Objective evidence of tumour regression has been reported in 68% of patients after castration-practically twice the response rate seen in females.Regression of soft-timue metastases from male breast cancer occurs more commonly than does control of bone metastases.According to the larger published series, the average duration of response to castration before reactivation of tumour is 29 months, but pain relief of bone metastases is sometimes maintained for several years.As in the female, the response to castration is better in males who show a longer recurrence-free interval after mastectomy.Prophylactic castration at the time of mastectomy is advisable in patients who are found to have invasion of the axillary nodes, in the hope of prolonging the recurrence-free interval.Corticosteroid therapy is usually advised when tumour con- trol by castration is lost.Palliation of symptoms results more frequently than after bilateral adrenalectomy or hypophysec- tomy in such cases, though occasional cases of tumour regression have been recorded after such major endocrine ablation.Oestrogen therapy also is occasionally effective in the management of advanced breast cancer in the male, and a tumour remission rate of 14% has been reported by one author.'As the primary method of therapy, it is not a reasonable alternative to castration, and, added to castration as primary therapy, it appears to add nothing to the tumour remission rate.Androgen administration, on the other hand, is said to exacerbate the growth of metastases from breast cancer.To summarize, endocrine therapy is essentially a palliative procedure which is effective in a minority of patients.The average duration of tumour growth control and increase in survival from most methods is from 12 to 24 months.Several methods can be used sequentially with additive results, as more than one is often successful in the same patient.By using the most suitable means of hormonal therapy for each individual the extra months of life can be useful and pain-free.On the other hand, it may not be justifiable to aim at extra months of life at the expense of severe physical or mental disability, or at the risk of a high operative mortality rate.