tbuckley/cabot-search huggingface dataset:
Complimentary transcriptomic-metallomic analysis identifies risk of relapse for clear-cell renal cell carcinoma (ccRCC) patients.
Authors: Shuchi Gulati, Bhargav Vemuri, Dina Secic, Behrouz Shamsaei, David R. Plas, John T. Cunningham, Jarek Meller, Julio Alberto Landero, Maria F. Czyzyk-Krzeska
Journal: Journal of Clinical Oncology (2022)

378 Background: Patients with localized or locally advanced ccRCC undergo surgical resection by partial or radical nephrectomy. Approximately 50% of tumors recur within five years after surgery. Currently the only FDA approved drug in the adjuvant setting is sunitinib. However, the absence of an overall survival benefit and the prevalence of side effects limit widespread use of sunitinib. Accurate identification of patients at high risk of recurrence would enhance targeted adjuvant therapy, while sparing low-risk patients from side effects. A single scoring system, transcriptomic signature or genomic classifier, is unlikely to accurately define prognosis. Here, we describe an integrated transcriptomic-metallomic classifier to assess the risk of relapse in localized ccRCC. Methods: We investigated the transcriptomic landscape of Caucasian male patients with stage III ccRCCs who remained disease free (S3DF) or relapsed (S3RL) within 24 months after surgery using the TCGA Firehose Legacy cohort. In a separate cohort of S3RL and S3DF ccRCCs, copper (Cu) content and molecular distribution were analyzed by size exclusion chromatography coupled to inductively coupled plasma mass spectrometry (SEC-ICP-MS). Results: Transcriptomic analysis identified that S3RL tumors were enriched for genes encoding subunits of mitochondrial electron transport chain (ETC) and mitochondrial ribosomal proteins (MRPs), an indication that mitochondrial activity may contribute to the relapse. In contrast, S3DF tumors were enrichedfor genes related to immune responses, including genes encoding members ofMHC-II, suggesting tumor control by the immune system. We established a setof 23 genes (23G) as a signature that stratified ccRCCsinto distinct groups characterized by low, intermediateand high risk of relapse after surgery. Importantly, SEC-ICP-MS analysis identified augmented distribution of Cu to the Cu cytochrome c oxidase complex (Cu-COX) in tumor mitochondria from S3RL, consistent with the prediction of increased ETC activity in the transcriptomic analysis. Conclusions: Integration of the 23G transcriptomic signature and Cu-COX complex measurements in locoregional ccRCC can serve as a prognostic biomarker for recurrence, and as a predictive classifier for novel treatments, including inhibitors of ETC for the S3RL tumors. In particular, a combination classifier using both measurements may have a stronger prognostic/predictive power as compared to either biomarker alone.
Abstract 204: Conventional vs. Compression-Only Cardiopulmonary Resuscitation for Geriatric Out-of-Hospital Cardiac Arrest
Authors: Hiroki Ueyama, Yosuke Homma, Hiroyasu Shimizu, Tetsuya Inoue, Hiraku Funakoshi
Journal: Circulation (2018)

Introduction: Compression-only cardiopulmonary resuscitation (CPR) and conventional CPR (30:2, chest compression and rescue breathing) performed by bystanders are known to have similar outcomes in adults. This study aimed to investigate if this difference is applicable in geriatric populations as well. Methods: We conducted a prospective observational study using the All-Japan Utstein Registry to enroll geriatric patients (≥75 years) who experienced out-of-hospital cardiac arrest that was witnessed by bystanders in Japan from January 1, 2009 to December 31, 2013. The primary outcome was favorable neurological function 1 month after the event, which was defined as a Cerebral Performance Category Scale score of 1 or 2. The secondary outcomes were return of spontaneous circulation (ROSC), 1-month survival, and favorable overall function 1 month after the event, which was defined as an Overall Performance Category Scale score of 1 or 2. Outcomes of compression-only CPR and conventional CPR were compared using multivariable logistic regression analyses. Results: Of the 58,072 enrolled patients, 13,248 (22.8%) received conventional CPR whereas 44,824 (77.2%) received compression-only CPR. Favorable neurological outcomes were achieved in 708 (5.3%) patients receiving CPR and 1799 (4.0%) patients receiving compression-only CPR. A crude analysis of neurologically favorable survival revealed superiority of conventional CPR [odds ratio (OR), 1.35; 95% confidence interval (CI), 1.24–1.48; P &lt; 0.001]], but it was no longer statistically significant after multivariable adjustment (OR, 1.09; 95% CI, 0.93–1.27; P = 0.29). Similarly, multivariable adjusted analysis of favorable overall function survival showed no significant difference (OR, 1.08; 95% CI, 0.92–1.26; P = 0.38) between conventional and compression-only CPR. Conventional CPR demonstrated better outcomes in multivariable adjusted analysis of ROSC and 1 month survival (OR, 1.30; 95% CI, 1.22–1.40; P &lt; 0.001 and OR, 1.13. 95% CI, 1.04–1.23; P = 0.003, respectively). Conclusions: The superiority of conventional CPR in geriatric populations was not proven. Thus, we conclude that compression-only CPR is an adequate means of resuscitation in geriatric populations.
The immunocytokine M9241 in the treatment of prostate cancer (PCa): Clinical and immune data from a phase 1 study.
Authors: Luke Meininger, Ravi Amrit Madan, Nicole Toney, Renee Nicole Donahue, Margaret Elena Gatti-Mays, Julius Strauss, Fatima Karzai, Marijo Bilusic, Jennifer L. Marte, Lisa M. Cordes, Jason Redman, Charalampos S. Floudas, Danielle M. Pastor, William Douglas Figg, William L. Dahut, Jeffrey Schlom, James L. Gulley
Journal: Journal of Clinical Oncology (2022)

127 Background: Interleukin-12 (IL-12) is a proinflammatory cytokine that plays a critical role in regulating the transition from innate to adaptive immunity but has toxicity with systemic administration. M9241 is an immunocytokine composed of 2 IL-12 heterodimers, each fused to one of the H-chains of the NHS76 antibody, which has affinity for both single and double stranded DNA. Thus, M9241 targets delivery to regions of tumor necrosis where DNA has become exposed. NCT01417546, a phase I trial of M9241 at escalating doses, established safety and dosing (Strauss J et al, CCR 2019). This was the first use of M9241 in human subjects with solid tumors including PCa. Methods: Nine patients (pts) with PCa enrolled in the phase 1 study, not all of which were presented previously. M9241 was given subcutaneously every 4 weeks (0.1-21.8mcg/kg) or every 2 weeks (12-16.8mcg/kg). PSA declines and immune responses were evaluated including systemic cytokine levels and 30 markers on 158 circulating immune cell subsets. Results: Nine PCa pts were treated with NHS-IL12 and 8 were evaluable for response, including 6 pts with biochemical recurrence and 2 with metastatic castration resistant prostate cancer (one patient discontinued the study treatment after 1 dose due to grade 3 elevation in ALT). There were no adverse events (AEs) of grade &gt;4. Additional grade 3 toxicities included one each of: leukopenia, neutropenia and lymphopenia. The most common AEs of any grade were lymphopenia (77.8%), fatigue (55.6%), and ALT elevation (55.6%). 5 of 8 (62.5%) had PSA declines ranging from 8-42%. After treatment with M9241, evaluable pts had increases in systemic IL-10, TNF and INFg. Additional immune changes included increases in activated subpopulation of natural killer (NK) cells, consistent with the phase 1 experience. Conclusions: M9241 was found to be safe and well tolerated in PCa pts. PSA declines occurred in 5 of 8 evaluable pts. As with the phase 1 study, increases in NK subpopulations were seen in the small number of evaluable pts. These preliminary findings of a necrosis-targeting immunocytokine will be evaluated further in combination studies with cytotoxic therapy. M9241 is currently being evaluated in combination with docetaxel in metastatic prostate cancer (NCT04633252). Clinical trial information: NCT01417546.
The Papanicolaou test in elderly women
Authors: D. E. Riesenberg
Journal: JAMA (1986)

Primary care physicians can have a major impact on the diagnosis and treatment of gynecologic malignancy in elderly women. Previous literature on the subject of Papanicolaou tests in the elderly has been confusing to physicians who must decide which screening procedures are appropriate for their patients. The study by Mandelblatt et al<sup>1</sup>in this issue ofThe Journalwill surely be welcome to such physicians. Prospectively evaluating over 800 elderly women, the authors found a prevalence rate for abnormal Papanicolaou smears (ranging from cervical intraepithelial neoplasia I to invasive carcinoma) of 16 per 1000 cervices at risk. Of equal importance is the fact that 47% of potential participants either refused to have a Papanicolaou smear or did not keep the follow-up appointment scheduled for that purpose. Nonparticipants, who less frequently reported having had a hysterectomy, appeared to be at greater risk for cervical neoplasia than participants. Also noteworthy is
Cases from Private Practice
Authors: J. R. Wardell
Journal: BMJ (1848)

INFANTICIDE.vomitings, but witbout other signs of constitutional dis.turbance.Under these s)mptoms I enquired if ahe had a rupture, to which she replied that she believed not, but on rubbing her bowels for relief she had then dis- covered a swelling in the groin.On examination, a tumour was discovered, of the size of a walnut, resting, on Poupart's ligament, midway between the symphisis pubis, and the spinous process of the ilium.This, however, was an enlarged gland, aud threw no light on the nature of her attack.Calomel, and the common purging mixture, with opium combined, were ordered forthwith, and anodyne fomentations to be applied to the belly, and the same repeated early in the morning, if necessary.31st. 10 a.m.AMy patient found some relief from the fomentations, but the medicines had aggravated the pain, and vomiting was more frequent, and attended with more pain.Finding therefore that anything of a drastric nature gave her this distress, I ordered her injections with castor oil, the saline aperient mixture, and pills withi calomel and opium, to be given every two hours alternate'ly. 5p.m.No improvement whlatever; and as the patient was mnch worn down by pain and continued retching, I thought it prudent to open a vein, in the hope that such an operation would render the aperients more efficacious.Fortunately, perhaps, for the patient, and owing to faintness, onlv three or four ounces were obtained.I then persevered in throwing up warm water, with a small quantity of castor oil, until at last two quarts were injected, and the fomentat.onswere ordered to be continued.November 1st, 9 a.m.I found the patient exceedinoly weak, part of the fluid injected returned, and a large quantity of dark-coloured fluid thrown off the stomach.
Corneal Transplantation
Authors: J. W. T. Thomas
Journal: BMJ (1937)

In this paper it is intended to present an account of the results of corneal transplantation as carried out by ophthalmic surgeons in recent years The numerous operations during the hundred years dating from the early par-t of the nineteenth century were nearly all failures, and will not be discussed in this paper.Opinion in this country was summarized by Sir John Parsons in his textbook Diseases of the Eye in 1924 in the following words:" Keratoplasty, or the excision of a small disk of scarred cornea, and its replacement by a disk of rabbit's or human cornea, is practically never successful; the transplanted tissue rapidly becomes opaquie."
Health-related quality of life (HRQoL) in previously untreated patients with advanced renal cell carcinoma (aRCC) in CheckMate 214: Five-year follow-up results.
Authors: David Cella, Toni K. Choueiri, Melissa Hamilton, Flavia Ejzykowicz, Steven I. Blum, Cristina Ivanescu, Robert J. Motzer
Journal: Journal of Clinical Oncology (2022)

307 Background: Nivolumab + ipilimumab (N+I) demonstrated durable, long-term survival in the phase 3 CheckMate 214 trial as first-line treatment for intermediate/poor (I/P)-risk patients (pts) with aRCC. After a minimum follow-up of 5 years, N+I maintained superior overall survival and response benefits vs sunitinib (S) in both I/P-risk pts and across all randomized pts. We report the HRQoL results from the 5-year follow-up. Methods: Pts were randomized 1:1 to receive N 3 mg/kg + I 1 mg/kg every 3 weeks (wks) for 4 cycles followed by N 3 mg/kg every 2 wks or S 50 mg/d orally for 4 wks (6-wk cycle). HRQoL was assessed using the FKSI-19, FACT-G, and EQ-5D-3L instruments at baseline (BL) and on day 1 of wks 1 and 4 of the first 2 cycles, on day 1 of wks 1 and 5 of the next 2 cycles, and on day 1 of wk 1 of subsequent cycles. The analyses included mixed-model repeated measures (MMRM) for change from BL across 59 months (while on-treatment) and time to confirmed deterioration (TCD). Bother with treatment side effects (item GP5 in FKSI-19) was assessed using a generalized estimating equations model with response dichotomized as minimal bother (“not at all” or “a little bit”) vs notable bother (“somewhat”, “quite a bit”, and “very much”). Results: 1096 pts were randomized to N+I (I/P-risk: 425; favorable [F]-risk: 125) and S (I/P-risk: 422; F-risk: 124). In the overall and I/P-risk populations, N+I pts reported improved mean FKSI-19 total scores over time compared with a decline observed with S. Overall changes from BL through 59 months favored N+I over S with significant differences between arms observed for all outcomes (Table). Median TCD was significantly longer with N+I vs S for all FKSI-19 scores, as well as FACT-G total and physical domains for both populations ( P &lt; 0.05). Pts in the N+I arm were 76% (odds ratio [95% CI]: 0.24 [0.16–0.35]) and 73% (0.27 [0.18–0.40]) less likely to be notably bothered by side effects than pts in the S arm in the total and I/P-risk populations, respectively. Conclusions: Pts reported HRQoL benefits with N+I vs S. Treatment with N+I showed a decreased risk of being bothered by treatment side effects and of experiencing clinically meaningful deterioration in HRQoL in contrast with S. These results suggest that the superior efficacy of N+I over S comes with the additional benefit of improved long-term HRQoL. Clinical trial information: NCT02231749. [Table: see text]
Abstract 17179: Blunted Vasoreactivity and Loss of Flow Reserve Contribute to Impaired Arteriogenesis in Diabetic Peripheral Artery Disease
Authors: XinLu Wang, Michael Simons, William Sessa, Zhen W Zhuang
Journal: Circulation (2018)

Introduction: Given the uncertainty around the exact pathophysiological mechanisms of diabetic peripheral artery disease (PAD), patients continue to have extremely poor prognoses. Our study attempted to address this critical unmet need. Hypothesis: We hypothesize that vasoreactivity in the feeding artery and impaired peripheral flow reserve are two primary causes of impaired arteriogenesis in these patients. Methods: The distal right femoral artery was ligated 2 weeks after streptozocin (STZ, n=12) or citrate buffer (n=12) treatment in wild-type (WT) mice. The contralateral hindlimbs were used as a negative control. 2 weeks post-hindlimb ischemia (HLI), the endothelial (EC)-dependent and EC-independent vasodilatation of the feeding artery was investigated using a Vevo 770 preclinical ultrasound scanner. Peripheral flow reserve was also assessed by pulse wave Doppler after 60 ul adenosine (3mg/ml) was administered systemically. A microCT angiography was performed to quantify collateral arteries. Gastrocnemius muscles were taken both for immunohistochemical examination in the evaluation of angiogenesis. Results: Femoral diameters at rest were similar between both control and diabetic models. In the non-ischemic limb, diabetes markedly blunted endothelial and smooth muscle cell (SMC) vasodilation reaction in the proximal femoral artery when compared with control mice [[acetylcholine (Ach): 286.3 ±16 μm versus 370±30 μm; sodium nitroprusside (SNP): 285±24.5 μm versus 350±30 μm, p&lt;0.01]. In the ischemic hindlimb, chronic ischemia impaired vasodilation in diabetic mice when compared with control mice (Ach: 255±16 μm versus 330±40 μm; SNP: 340±50 μm versus 253±22 μm, p&lt;0.05). In diabetic mice, peripheral flow reserve was impaired (1.27±0.27 in controls vs 0.87±0.13 in diabetes, p&lt;0.05), with arteriole rarefaction and increased capillary/muscle ratio. Conclusions: This study demonstrated that chronic hyperglycemia negatively affects collateral development at different levels: 1 ) dysregulation of the feeding artery; 2 ) impaired arteriogenesis and increased angiogenesis; and 3 ) loss of peripheral flow reserve.
Effect of post-operative goal-directed fluid therapy (GDFT) on organ function after orthotopic liver transplantation: Secondary outcome analysis of the COLT randomised control trial
Authors: Farid Froghi, Vignesh Gopalan, Zachos Anastasiou, Rahul Koti, Kurinchi Gurusamy, Christine Eastgate, Margaret McNeil, Helder Filipe, Manuel Pinto, Jeshika Singh, Louise Longworth, Susan Mallett, Nick Schofield, Douglas Thorburn, Daniel Martin, Brian R Davidson
Journal: International Journal of Surgery (2022)
Filariasis
Authors: G. Melton, E. Montuschi
Journal: BMJ (1948)

For these reasons, then, I regard all cases of phantom pain as being similar in origin and mechanism of production, whether they have burning pain or not.It is, however, possibly not altogether desirable for the word " causalgia " to be used to describe all these cases, with their varying painful sensations, or even for the term "minor causalgia " to be used for the less severe examples.As pointed out by Dr. Bowden and Dr. Napier, Weir Mitchell originally coined the word " causalgia," meaning literally " fire pain," to describe only the single symptom of burning pain; and it might still be desirable to use it only in this sense, or at least only for cases with this type of pain, without of course implying that there is any difference in pathogenesis between this " causalgic ' pain and lesser degrees of pain following nerve trauma.-Iam, etc., Belfast.
Lectures on Orthopaedic Surgery
Authors: B. E. Brodhurst
Journal: BMJ (1863)

SCOIOSIS, or Lateral Curvature of the Spine, is that distortion in which the vertebrae deviate, as the term implies, in a lateral direction away from the mesial line of the trunk.This affection may be divided into two stages, or periods ; namely, first, incipient curvature; and se- condly, conjir'med lateral curvature.It is important that these terms should be rightly understood; and I would, therefore, define thenm thus.Incipient curvature is removable in the hori- zontal position, either by slight lateral pressure or even by throwing certain muscles into action ; while a confirmed curve requires long-continued mechani- cal means to effect the same object.
Lung directed antibody gene transfer confers protection against SARS-CoV-2 infection
Authors: Yue Du, Kamran M Miah, Omar Habib, Helena Meyer-Berg, Catriona C Conway, Mariana A Viegas, Rebecca Dean, Dwiantari Satyapertiwi, Jincun Zhao, Yanqun Wang, Nigel J Temperton, Toby P E Gamlen, Deborah R Gill, Stephen C Hyde
Journal: Thorax (2022)

Background The COVID-19 pandemic continues to be a worldwide threat and effective antiviral drugs and vaccines are being developed in a joint global effort. However, some elderly and immune-compromised populations are unable to raise an effective immune response against traditional vaccines. Aims We hypothesised that passive immunity engineered by the in vivo expression of anti-SARS-CoV-2 monoclonal antibodies (mAbs), an approach termed vectored-immunoprophylaxis (VIP), could offer sustained protection against COVID-19 in all populations irrespective of their immune status or age. Methods We developed three key reagents to evaluate VIP for SARS-CoV-2: (i) we engineered standard laboratory mice to express human ACE2 via rAAV9 in vivo gene transfer, to allow in vivo assessment of SARS-CoV-2 infection, (ii) to simplify in vivo challenge studies, we generated SARS-CoV-2 Spike protein pseudotyped lentiviral vectors as a simple mimic of authentic SARS-CoV-2 that could be used under standard laboratory containment conditions and (iii) we developed in vivo gene transfer vectors to express anti-SARS-CoV-2 mAbs. Conclusions A single intranasal dose of rAAV9 or rSIV.F/HN vectors expressing anti-SARS-CoV-2 mAbs significantly reduced SARS-CoV-2 mimic infection in the lower respiratory tract of hACE2-expressing mice. If translated, the VIP approach could potentially offer a highly effective, long-term protection against COVID-19 for highly vulnerable populations; especially immune-deficient/senescent individuals, who fail to respond to conventional SARS-CoV-2 vaccines. The in vivo expression of multiple anti-SARS-CoV-2 mAbs could enhance protection and prevent rapid mutational escape.
Abstract 257: Unselective Pulmonary Vasodilation is an Important Factor in Sodium Nitroprusside Enhanced Cardiopulmonary Resuscitation Improved Blood Flow
Authors: Adrian Ripeckyj, Kadambari Chandra Shekar, Sebastian Voicu, Jennifer Rees, Timothy Matsuura, Jason A Bartos, Demetris Yannopoulos
Journal: Circulation (2018)

Introduction: Sodium nitroprusside enhanced CPR (SNPeCPR) is a novel CPR method that includes a potent vasodilator, active compression-decompression CPR, an inspiratory impedance threshold device and abdominal binding. SNPeCPR has been shown to improve vital organ flow and functional survival outcomes compared to standard CPR methods in animals. We hypothesize that one of the main effects of SNPeCPR mediated increase in cardiac output during prolonged resuscitation is profound pulmonary artery vasodilation. Methods: After electrically induced VF was left untreated for 3 min, 20 (44-48Kg) pigs were randomized to receive SNPeCPR (10) or standard CPR (10) for a total of 30 min; the first 10 minutes were BLS CPR followed by twenty minutes of ACLS. During ACLS, animals were given IV SNP (1mg bolus) or standard epinephrine (0.5mg) q5 min until ROSC or 45 min total CPR. Shocks were delivered after 30 minutes of CPR at 300J. If ROSC was achieved, animal was monitored until 4-hour endpoint. Ventilations were provided with 10ml/kg at 10/min with a mechanical ventilator. Initially during CPR, room air was used and FiO2 was adjusted q5 minutes to maintain O 2 %saturation &amp;gt 92% based on ABG. Lactic acid was also measured. Aortic, right atrial, and coronary artery pressures and carotid blood flow were recorded continuously. A-a oxygen gradient was measured with standard technique. Results: SNPeCPR animals documented a significantly higher mean CPP, lower lactic acid and 3x higher carotid blood flow over 30 minutes compared to standard CPR as previously documented. A-a oxygen gradient was dramatically increased in the SNPeCPR and coincided with a decreased lactate level (see Figure 1). Discussion: SNPeCPR causes profound pulmonary vasodilation and increases flow through non-ventilated lung areas. Despite that, the overall increase in forward flow leads to higher minute O 2 delivery and improved tissue perfusion. SNPeCPR should be used with 100% oxygen in the first human clinical trial.
International Symposium on Detection and Treatment of Minimal Residual Disease in Acute Leukemia
Journal: JNCI Journal of the National Cancer Institute (1985)

International Symposium on Detection and Treatment of Minimal Residual Disease in Acute Leukemia Get access JNCI: Journal of the National Cancer Institute, Volume 74, Issue 6, June 1985, Pages 1365–1366, https://doi.org/10.1093/jnci/74.6.1365-d Published: 01 June 1985