tbuckley/cabot-search huggingface dataset:
The effect of zoledronic acid (Zol) dose and infusion rate on pharmacokinetics (PK), pharmacodynamics (PD), and renal function in patients (pts) with multiple myeloma (MM) or prostate cancer (PC) and bone metastases
Authors: P. P. Major, J. Berenson, R. Swift, R. Vescio, C. Ravera, S. Bilic, S. Gauron, J. Denouel, H. Schran
Journal: Journal of Clinical Oncology (2005)

2079 Background: Zol has demonstrated efficacy and safety in the treatment of bone lesions in pts with MM and other solid tumors. This phase I open-label study investigated the PK, PD, and safety of monthly infusions of Zol (4, 8, or 12 mg), using an infusion rate model predicted to yield a Cmax similar to that for 4 mg over 15 min. Methods: Pts received up to 6 doses of Zol q28 days: 4 mg via 15-min infusion on day 1; 8 mg via 60-min infusion on day 29 and 57; 12 mg via 120-min infusion on day 85 and 113; and 4 mg via 15-min infusion on day 141. Assessment of PK, PD, and safety was performed after each dose. Results: 20 pts (10 MM and 10 PC) were enrolled, and 14 completed 6 infusions (1 MM pt withdrew consent, 2 MM pts had abnormal lab values, 1 PC pt died, and 2 PC pts had grade 3/4 adverse events [AEs]). Median age was 57.5 yrs for MM pts and 70.5 yrs for PC pts. ECOG PS was ≤ 1 in 19 pts. All pts had received prior antineoplastic therapy. Zol was generally well tolerated; the most commonly reported AEs were fatigue (55%), bone pain (50%), nausea (45%), and myalgia/arthralgia (30% each). Transient serum creatinine increases from baseline occurred in 3 MM pts, resulting in dose delay/decrease (n = 1) or discontinuation after infusion 5 (n = 2). No PC pts had elevated serum creatinine from baseline. Clinically significant (grade 3/4) non-renal-related AEs occurred in 9 pts. In MM pts, mean Cmax(± SD) was 329 (± 89) ng/mL after the first 4-mg dose (1st infusion), 407 (± 105) ng/mL after the 2nd 8-mg dose (3rd infusion), and 385 (± 114) ng/mL after the 2nd 12-mg dose (5th infusion). These were nearly identical to model-predicted values. Mean observed AUC0–24h(± SD) in MM pts was 589 (± 181) ng · h/mL after the 1st infusion, 1,489 (± 451) ng · h/mL after the 3rd infusion, and 1,896 (± 591) ng · h/mL after the 5th infusion. In comparison, Cmax and AUC were consistently 25% to 40% lower in PC pts. Conclusions: Zol was well tolerated at doses of 8 and 12 mg infused over 60 and 120 min, respectively, and the model-predicted Cmax was achieved. This study provides a rationale for investigating Zol at doses ≥ 4 mg infused over > 15 min in a broader clinical trial. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Millennium, Novartis Novartis Millennium, Novartis
Proteomic Profile of Human Gut Biopsies from Celiac Patients with and without Severe Complications.
Authors: Michele Spina, Vallì De Re, Maria Paola Simula, Laura Caggiari, Nicoletta Orzes, Alessandro Da Ponte, Leandro Apollonia, Riccardo Dolcetti, Alfonso Colombatti, Vincenzo Canzonieri, Renato Cannizzaro
Journal: Blood (2006)
IDH1 and IDH2 Mutations Confer An Adverse Effect In Patients With Acute Myeloid Leukemia Lacking The NPM1 Mutation
Authors: Shunichiro Yamaguchi, Eisaku Iwanaga, Kenji Tokunaga, Tomoko Nanri, Taizo Shimomura, Hitoshi Suzushima, Yutaka Okuno, Hiroaki Mitsuya, Norio Asou
Journal: Blood (2013)
Points raised in responses
Authors: Sharon Davies
Journal: BMJ (2007)

We select the letters for these pages from the rapid responses posted on bmj.com favouring those received within five days of publication of the article to which they refer.Letters are thus an early selection of rapid responses on a particular topic.Readers should consult the website for the full list of responses and any authors' replies, which usually arrive after our selection. DaviD Mcarthy
Crushed Prasugrel Tablets in Patients With STEMI Undergoing Primary Percutaneous Coronary Intervention
Authors: Fabiana Rollini, Francesco Franchi, Jenny Hu, Megha Kureti, Niti Aggarwal, Ashwin Durairaj, Yongwhi Park, Michael Seawell, Pedro Cox-Alomar, Martin M. Zenni, Luis A. Guzman, Siva Suryadevara, Patrick Antoun, Theodore A. Bass, Dominick J. Angiolillo
Journal: Journal of the American College of Cardiology (2016)

Platelet inhibitory effects induced by oral P2Y12 receptor antagonists are delayed in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI), which may be attributed to impaired absorption affecting drug pharmacokinetics (PK) and pharmacodynamics (PD). Crushing tablets has been suggested to lead to more favorable PK/PD profiles. To date, no studies have investigated the PK/PD effects of crushing prasugrel.This study sought to determine whether crushing prasugrel is associated with more favorable drug bioavailability and platelet inhibitory effects compared with whole tablets in STEMI patients undergoing PPCI.Our prospective, randomized, open-label study assessed STEMI patients undergoing PPCI (n = 52) who were treated with a prasugrel 60-mg loading dose (LD) either as whole or crushed tablets. PK/PD analyses were performed at 7 time points. PD effects were measured as P2Y12 reaction units and platelet reactivity index, and PK by plasma levels of prasugrel's active metabolite.Compared with whole tablets, crushed prasugrel led to reduced P2Y12 reaction units by 30 min post-LD, which persisted at 1, 2 (164 vs. 95; least square mean difference = 68; 95% confidence interval: 10 to 126; primary endpoint), and 4 h post-LD. Significant differences were no longer present at 6 h post-LD. Parallel findings were shown with platelet reactivity index. Accordingly, high on-treatment platelet reactivity rates were reduced with crushed prasugrel. PK analyses showed a >3-fold faster absorption with crushed compared with whole prasugrel.In STEMI patients undergoing PPCI, crushed prasugrel leads to faster drug absorption, and consequently, more prompt and potent antiplatelet effects compared with whole tablet ingestion. (Pharmacological Effects of Crushing Prasugrel in STEMI Patients; NCT02212028).
CXCR1-mediated neutrophil degranulation and fungal killing promote <i>Candida</i> clearance and host survival
Authors: Muthulekha Swamydas, Ji-Liang Gao, Timothy J. Break, Melissa D. Johnson, Martin Jaeger, Carlos A. Rodriguez, Jean K. Lim, Nathaniel M. Green, Amanda L. Collar, Brett G. Fischer, Chyi-Chia Richard Lee, John R. Perfect, Barbara D. Alexander, Bart-Jan Kullberg, Mihai G. Netea, Philip M. Murphy, Michail S. Lionakis
Journal: Science Translational Medicine (2016)

CXCR1 as a mediator of neutrophil fungal killing and host defense against systemic fungal infection in mice and humans.
Impact of Platinum Agent [Cisplatin (Cis) or Carboplatin (Ca)] in First-Line Chemotherapy (Ct) on Overall Survival in Metastatic Urothelial Carcinoma (Muc) Patients (Pts): a Retrospective Study
Authors: M. Auvray, Y. Vano, P. Combe, R. Elaidi, E. Auclin, C. Takouchop, J. Medioni, F. Scotte, S. Oudard
Journal: Annals of Oncology (2014)
Abstract 278: A Pilot Study Examining the Role of Regional Cerebral Oxygen Saturation Monitoring as a Marker of Return of Spontaneous Circulation in the Shockable and Nonshockable Causes of Cardiac Arrest
Authors: Anna Ahn, Asad Nasir, Francis Dorazi, Hanan Malik, Sam Parnia
Journal: Circulation (2012)

Background: To date there has been no reliable “real time” monitoring available to determine the adequacy of oxygen delivery and cerebral perfusion during cardiac arrest. Although, we have previously demonstrated that the mean regional cerebral oxygen saturation (rSO2) measured by cerebral oximetry can be used to determine return of spontaneous circulation in cardiac arrest, the rSO2 level that corresponds with ROSC in the 3 main different subtypes of cardiac arrest (VF/VT, PEA, asystole has not been examined. Objectives: To investigate the level of rSO2 that corresponds with ROSC in 1) VF/VT, 2) PEA and 3) asystole subtypes of cardiac arrest using a commercially available cerebral oximeter (Equanox, Nonin, USA) Methods: Cerebral oximetry was applied to 34 in-hospital cardiac arrest patients and continuous data was collected until either ROSC was achieved or CPR was terminated. Results: Overall 20 patients achieved ROSC, whereas 14 did not. There was a significant overall difference in mean±SD rSO2% in patients who achieved ROSC (49.7 ± 11.3% vs. 33.9 ± 15.0% p=&lt;0.001) compared to those who did not. Examination of the cardiac arrest subtypes revealed that while this difference was observed in the PEA (n=13) 54.6 ± 8.7 vs. 36.8 ± 20.4 (p=&lt;0.05) and asystole (n=16) 46.6 ± 11.4 vs. 27.4 ± 10.8 (p=&lt;0.05) subgroups, there was no difference in rSO2 in patients with and without ROSC in the VF/VT subgroup (n=5) 41.6 ± 18.5 vs. 45.0 ± 11.6 (p=0.8). Conclusions : Although cerebral oximetry may be used as a real-time non-invasive marker of ROSC during cardiac arrest, the main difference in rSO2 between patients achieving ROSC and those without ROSC applies to the asystole and PEA sub groups of cardiac arrest, rather than VF/VT. This likely reflects the different dominant physiological disorders between shockable and non-shockable causes of cardiac arrest. Whereas recovery from PEA and asystole is dependent on the adequacy of oxygen delivery, recovery from VF/VT predominantly relates to the timing of defibrillation.
RASSF1A Directly Antagonizes RhoA Activity through the Assembly of a Smurf1-Mediated Destruction Complex to Suppress Tumorigenesis
Authors: Min-Goo Lee, Seong-In Jeong, Kyung-Phil Ko, Soon-Ki Park, Byung-Kyu Ryu, Ick-Young Kim, Jeong-Kook Kim, Sung-Gil Chi
Journal: Cancer Research (2016)

RASSF1A is a tumor suppressor implicated in many tumorigenic processes; however, the basis for its tumor suppressor functions are not fully understood. Here we show that RASSF1A is a novel antagonist of protumorigenic RhoA activity. Direct interaction between the C-terminal amino acids (256-277) of RASSF1A and active GTP-RhoA was critical for this antagonism. In addition, interaction between the N-terminal amino acids (69-82) of RASSF1A and the ubiquitin E3 ligase Smad ubiquitination regulatory factor 1 (Smurf1) disrupted GTPase activity by facilitating Smurf1-mediated ubiquitination of GTP-RhoA. We noted that the RhoA-binding domain of RASSF1A displayed high sequence homology with Rho-binding motifs in other RhoA effectors, such as Rhotekin. As predicted on this basis, RASSF1A competed with Rhotekin to bind RhoA and to block its activation. RASSF1A mutants unable to bind RhoA or Smurf1 failed to suppress RhoA-induced tumor cell proliferation, drug resistance, epithelial-mesenchymal transition, migration, invasion, and metastasis. Clinically, expression levels of RASSF1A and RhoA were inversely correlated in many types of primary and metastatic tumors and tumor cell lines. Collectively, our findings showed how RASSF1A may suppress tumorigenesis by intrinsically inhibiting the tumor-promoting activity of RhoA, thereby illuminating the potential mechanistic consequences of RASSF1A inactivation in many cancers. Cancer Res; 76(7); 1847-59. ©2016 AACR.
Tryptophan depletion and attenuation of cue-induced craving for cocaine
Authors: S L Satel, J H Krystal, P L Delgado, T R Kosten, D S Charney
Journal: American Journal of Psychiatry (1995)

Although cocaine is a potent serotonin (5-HT) reuptake blocker, the role of 5-HT systems in cocaine craving and relapse in humans has been unclear. The authors evaluated whether acute reductions in central 5-HT synthesis modulated craving for cocaine in cocaine-dependent patients.Twenty-five cocaine-dependent male inpatients were exposed to cocaine-craving cues while their 5-HT levels were lowered and during a placebo condition in a counterbalanced, double-blind design. 5-HT levels were reduced by rapidly lowering plasma levels of its precursor, tryptophan; tryptophan levels were reduced by stimulating protein synthesis with a large drink of amino acids devoid of tryptophan. During the placebo condition the patients drank an identical amino acid drink containing tryptophan. Craving was induced by exposing patients to cocaine paraphernalia and a videotape depicting drug use. Craving was assessed 7 hours after ingestion of the drink. Visual analog ratings of craving for cocaine were administered before and after cue exposure at each test session.Patients reported less desire for cocaine stimulated by cue exposure after drinking amino acids without tryptophan than they did after drinking placebo. The order that tryptophan depletion and placebo tests were performed influenced the impact of tryptophan depletion on cue-induced craving.Serotonergic systems modulate cue-induced craving for cocaine, a factor implicated in relapse to cocaine use.
Posaconazole Substitution for Voriconazole-Associated Phototoxic Effects
Authors: Audrey A. Jacobsen, Yotam B. Papo, Robert Sarro, Kurt Weisse, John Strasswimmer
Journal: JAMA Dermatology (2016)

of 18 serious AEs occurred, 7 of which were judged to be drug related.These included pyrexia, lymphopenia (n = 2), spondylitis, staphylococcal sepsis, rhabdomyolysis, and thrombocytopenia.Four deaths were reported but not considered studydrug related.Discussion | In previous studies, APO866 induced cell death at low concentration in human hematologic malignancy cells, including lymphomas. 5 No resistance mechanisms are known.In the present study, APO866 showed a reasonable toxic effect in CTCL.Severe lymphocytopenia and thrombocytopenia were observed, and the other AEs were mild to moderate.However, the drug was not powerful enough, and the study was stopped early after the prespecified interim analysis owing to lack of drug efficacy.For these reasons, we do not see a justification for further development of APO866 in CTCL.However, owing to its mode of action with immunosuppression and insulin-mimicking effects, APO866 might play a role the treatment of other conditions.
Tuberculosis—advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers
Authors: Robert S Wallis, Markus Maeurer, Peter Mwaba, Jeremiah Chakaya, Roxana Rustomjee, Giovanni Battista Migliori, Ben Marais, Marco Schito, Gavin Churchyard, Soumya Swaminathan, Michael Hoelscher, Alimuddin Zumla
Journal: The Lancet Infectious Diseases (2016)
A new variant of the heat shock protein GRP78 as target for antibody- treatment of pancreatic cancer
Authors: H. Vollmers, N. Rauschert, L. Rasche, F. Hensel, S. Brändlein
Journal: Journal of Clinical Oncology (2007)

21173 Background: Pancreatic malignancies belong to the top-five killers among all cancers worldwide. The 5-year survival rate with conventional therapy is below 5%. This shows that there is a big need for new therapeutical approaches. The fully human monoclonal antibody SAM-6 is a germ-line coded IgM, isolated from a cancer patient by TRIOMA technology. SAM-6 antibody binds to a modified O-linked carbohydrate moiety expressed on a membrane-bound variant of GRP78, which is a member of the HSP70 family. Heat-shock proteins (HSPs) are critical components of a cell's defense mechanism against injury associated with adverse stresses. They can protect cells against subsequent, otherwise lethal, outcome. Although HSPs are very beneficial to the normal cell, cancer cells often over-express HSPs on the membrane. They use them in response to stresses associated with various therapies, diminishing the treatment effects. Methods: In vitro and in vivo assays were used to investigate the apoptotic effects of antibody SAM-6 on pancreas cancer cells. Results: Binding of SAM-6 antibody to GRP78 induces an overfeeding of malignant cells with oxidized LDL. The cancer cells over-accumulate depots of cholesterol and triglyceride esters and finally undergo apoptosis. The deadly effect of SAM-6 could be demonstrated in vitro and in vivo in experimental animal models. Conclusions: These data show that cancer-specific modifications of cell surface protection molecules are ideal targets for immuno-therapeutical approaches. No significant financial relationships to disclose.
Psychiatric diagnosis before serological testing for the human immunodeficiency virus
Authors: S Perry, L B Jacobsberg, B Fishman, A Frances, J Bobo, B K Jacobsberg
Journal: American Journal of Psychiatry (1990)

To identify the diagnostic characteristics and counseling needs of individuals at risk for acquired immune deficiency syndrome (AIDS), standardized DSM-III-R diagnoses were given to 207 physically asymptomatic adults when they sought serological testing for the human immunodeficiency virus (HIV). The subjects had high lifetime rates of mood disorders. Even after the 20 subjects with intravenous drug use as a risk factor were eliminated, lifetime rates of nonalcohol substance dependence were also high. These findings suggest that even before they are notified of HIV test results, many individuals at perceived risk for AIDS may be vulnerable to future depression and nonintravenous drug abuse.
Clinical outcomes following immediate reconstruction and post-mastectomy radiation therapy
Authors: J. D. Jhaveri, I. Savetsky, J. L. Bosworth, S. C. Rush
Journal: Journal of Clinical Oncology (2006)

10560 Background: Post-mastectomy radiation therapy (PMRT) is an important component of the treatment for locally advanced breast cancer. Some patients opt for immediate breast reconstruction (IR) to cope with the aesthetic consequences of mastectomy. A small number of series have reported mixed results with IR using a tissue expander/implant (TE/I) followed by PMRT. We sought to determine the outcome of patients receiving PMRT after IR with either TE/I or autologous tissue reconstruction (ATR), with respect to both complications and cosmesis. Methods: We retrospectively reviewed the charts of 47 women who underwent PMRT in our practice after IR. All follow-up information was obtained by reexamination or by telephone interview. Contracture/fibrosis results were scored on a scale as follows: 0- no complaints, 1- mild discomfort, not affecting activities of daily life (ADLs), 2- moderate discomfort, affecting ADLs, or biopsy-proven fat necrosis, 3- complications requiring surgical revision, 4- reconstruction failure, requiring removal. For cosmesis, results were recorded as: 1- acceptable, 2- unacceptable. Results: A total of 47 patients were identified as having undergone PMRT after IR. 35 underwent TE/I and 12 underwent ATR, most commonly transverse rectus abdominus muscle flap reconstruction. Median follow-up was 36 months (range: 26 - 96 months). All patients were treated with 50.4 Gy in 25 fractions to the chest wall, and seven patients received an additional electron boost to high risk areas. All patients received 45 Gy in 25 fractions to a supraclavicular field. Of the patients who underwent TE/I and PRMT, twenty-one of 35 (60%) described unacceptable cosmesis, as opposed to two of 12 ATR patients (17%) (p = .02). Similarly, 13 patients in the TE/I (37%) group required either surgical revision (n = 3) or complete removal of their implant (n = 10), as compared to none of the patients in the ATR group (p = .02). Conclusion: Immediate TE/I reconstruction with PMRT was associated with high rates of complications and poor cosmetic results in our experience. ATR resulted in significantly higher rates of functional and cosmetic success. Thus, if IR is planned in the setting of PMRT, ATR should be recommended. No significant financial relationships to disclose.
MicroRNA‐122 regulates polyploidization in the murine liver
Authors: Shu‐hao Hsu, Evan R. Delgado, P. Anthony Otero, Kun‐yu Teng, Huban Kutay, Kolin M. Meehan, Justin B. Moroney, Jappmann K. Monga, Nicholas J. Hand, Joshua R. Friedman, Kalpana Ghoshal, Andrew W. Duncan
Journal: Hepatology (2016)

A defining feature of the mammalian liver is polyploidy, a numerical change in the entire complement of chromosomes. The first step of polyploidization involves cell division with failed cytokinesis. Although polyploidy is common, affecting ∼90% of hepatocytes in mice and 50% in humans, the specialized role played by polyploid cells in liver homeostasis and disease remains poorly understood. The goal of this study was to identify novel signals that regulate polyploidization, and we focused on microRNAs (miRNAs). First, to test whether miRNAs could regulate hepatic polyploidy, we examined livers from Dicer1 liver‐specific knockout mice, which are devoid of mature miRNAs. Loss of miRNAs resulted in a 3‐fold reduction in binucleate hepatocytes, indicating that miRNAs regulate polyploidization. Second, we surveyed age‐dependent expression of miRNAs in wild‐type mice and identified a subset of miRNAs, including miR‐122, that is differentially expressed at 2‐3 weeks, a period when extensive polyploidization occurs. Next, we examined Mir122 knockout mice and observed profound, lifelong depletion of polyploid hepatocytes, proving that miR‐122 is required for complete hepatic polyploidization. Moreover, the polyploidy defect in Mir122 knockout mice was ameliorated by adenovirus‐mediated overexpression of miR‐122, underscoring the critical role miR‐122 plays in polyploidization. Finally, we identified direct targets of miR‐122 ( Cux1 , Rhoa , Iqgap1 , Mapre1 , Nedd4l , and Slc25a34 ) that regulate cytokinesis. Inhibition of each target induced cytokinesis failure and promoted hepatic binucleation. Conclusion: Among the different signals that have been associated with hepatic polyploidy, miR‐122 is the first liver‐specific signal identified; our data demonstrate that miR‐122 is both necessary and sufficient in liver polyploidization, and these studies will serve as the foundation for future work investigating miR‐122 in liver maturation, homeostasis, and disease. (H epatology 2016;64:599‐615)
B Cells Promote Pancreatic Tumorigenesis
Authors: Ali Roghanian, Christopher Fraser, Marianna Kleyman, Jianzhu Chen
Journal: Cancer Discovery (2016)

Abstract Summary: Three recent studies, approaching the question from different angles and using different and/or overlapping models, provide compelling evidence for the involvement of tumor-infiltrating B cells in the initiation and progression of pancreatic ductal adenocarcinoma. These studies highlight the need for a better understanding of pancreatic tumor–immune system interactions and the immunologic mechanisms that promote or inhibit tumorigenesis, paving the way for better treatment strategies. Cancer Discov; 6(3); 230–2. ©2016 AACR. See related article by Pylayeva-Gupta et al., p. 247. See related article by Lee et al., p. 256. See related article by Gunderson et al., p. 270.
Therapy for Secondary CNS Involvement in Malignant Lymphomas: No Standard Yet!
Authors: Agnieszka Korfel, Marc Chamberlain, Ed Neuwelt, Eckhard Thiel, Nancy Doolittle, Uwe Schlegel, Martin Dreyling, James Rubenstein, Lars Fischer, Magnus Björkholm, Peter Martus, Michael Weller, Michael Glantz
Journal: Journal of Clinical Oncology (2016)
"Hidden" eating disorders in Scottish psychiatric inpatients
Authors: S P Kutcher, A M Whitehouse, C P Freeman
Journal: American Journal of Psychiatry (1985)

The authors designed a study to determine the prevalence of "hidden" eating disorders among a large group of hospitalized psychiatric patients. Of 146 patients surveyed, 13.8% currently had eating disorders diagnosed according to DSM-III criteria: 7.3% had bulimia, 3.6% had anorexia nervosa, and 2.9% had an atypical disorder. Eighty percent of the bulimic patients and all of the patients with an atypical disorder had not been so identified by hospital diagnosis. Eating-disordered patients tended to have concurrent diagnoses of affective or personality disorders.