tbuckley/cabot-search huggingface dataset:
The Activation of MAPK in Melanoma Cells Resistant to BRAF Inhibition Promotes PD-L1 Expression That Is Reversible by MEK and PI3K Inhibition
Authors: Xiaofeng Jiang, Jun Zhou, Anita Giobbie-Hurder, Jennifer Wargo, F. Stephen Hodi
Journal: Clinical Cancer Research (2012)

Selective BRAF inhibition (BRAFi) provides a paradigm shift for melanoma treatment. The duration of benefit is typically limited before resistance develops. Interest remains in combining targeted and immune therapies to overcome resistance and improve durability of clinical benefit. One mechanism of evading immune destruction is programmed death-1-ligand 1 (PD-L1) expression by tumors that results in potent antitumor immune suppression.BRAFi-resistant melanoma cells were examined for changes in PD-L1 expression by immunoblot and flow cytometry. Signaling pathways involved in altering PD-L1 expression were examined. Strategies to maximize the effect of the BRAFi therapy were studied including MEKi, MEKi combinations, and additional pathways including phosphoinositide-3 kinase (PI3K).Melanoma cells resistant to BRAFi exhibit increased MAPK signaling and promotion of PD-L1 expression. PD-L1 expression is transcriptionally modulated by c-Jun and augmented by STAT3. MEK inhibition (MEKi) regains downregulation of MAPK signaling and suppresses the production of PD-L1. MEKi in melanoma cells shows dual therapeutic effects with simultaneous suppression of PD-L1 expression and induction of apoptosis. By combining MEKi with BRAFi, an additive effect on the inhibition of PD-L1 expression results.We report a novel mechanism that suppresses preexisting immune responses in patients with melanoma receiving BRAFi therapy. BRAFi resistance leads to increased expression of PD-L1 in melanoma cells, mediated by c-Jun and STAT3. MEKi may be feasible to counteract BRAFi resistance of MAPK reactivation and also for the additive effect of PD-L1 suppression. Potential therapeutic benefits of combining targeted inhibitors and immune modulation to improve patient outcomes should be investigated.
Does Homeostatic Pressure Explain Tumor Growth?
Authors: Mike Martin
Journal: JNCI Journal of the National Cancer Institute (2009)

T o the much-studied genetic and biochemical forces that govern cell growth, dysplasia, and metastasis, a burgeoning science — call it mechanical biology — is adding forces that might seem more applicable to airliners and skyscrapers. Shear, friction, stress, tension, and viscosity also play a role in oncogenesis, according to researchers exploring this interface between biology and physics. “To grow, a tumor must, most of the time, push normal tissue out of its natural position,” said Jacques Prost, Ph.D. , of the Curie Institute in Paris, a leader in the physical sciences research department where Pierre and Marie Curie discovered radium and Paul Langevin discovered sonar. “Mechanical forces are at work, hence the necessity of investigating their importance.” In a new report, Prost and his colleagues propose a mathematical model, based on existing clinical and laboratory data, that explains how a mechanical force that they call homeostatic pressure affects tumor growth and metastasis. Writing in the American Institute of Physics HFSP Journal, the physicists argue that analyzing cancer strictly on the basis of DNA abnormalities or chemical on – off switches cannot fully account for clinical and experimental data. The authors claim that their approach could lead to “a quantitative, experimentally accessible measure for the metastatic potential of early malignant growths.” “Genes do not move matter — physical mechanisms and processes do,” said Gabor Forgacs, Ph.D., a professor of biological physics and biomedical engineering at the University of Missouri, Columbia. Summing up the argument for investigating the physics of carcinogenesis, Forgacs said the Prost group’s analysis “illustrates how simple physical concepts like pressure can be applied to the ultimate intricate biological system: the tumor.”
Preoperative Inspiratory Muscle Training and Postoperative Complications
Authors: William C. Culp, Erik A. Beyer
Journal: JAMA (2007)

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
Resources dimorphism sexual selection and mathematics achievement
Authors: Diana Eugenie Kornbrot
Journal: Behavioral and Brain Sciences (1996)

Abstract Geary's model is a worthy effort, but ambiguous on important issues. It ignores differential resource allocation, although this follows directly from sexual selection via differential parental investment. Dimorphism in primary traits is arbitrarily attributed to sexual selection via intramale competition, rather than direct evolutionary pressures. Dubious predictions are made about the consequences of raising mathematics achievement.
Asthma and biofilm-forming bacteria are independently associated with revision sinus surgeries for chronic rhinosinusitis
Authors: Zi Zhang, Darren R. Linkin, Brian S. Finkelman, Bert W. O’Malley, Erica R. Thaler, Laurel Doghramji, David W. Kennedy, Noam A. Cohen, James N. Palmer
Journal: Journal of Allergy and Clinical Immunology (2011)
Multiple drafts: An eternal golden braid?
Authors: Daniel Dennett, Marcel Kinsbourne
Journal: Behavioral and Brain Sciences (1995)

Abstract Glicksohn and Salter both raise good questions that force us to clarify our position. We agree with much of their commentary, with a few caveats. Glicksohn wrongly assumes that later drafts must be “more advanced” and Salter speaks of “recruitment into consciousness,” which invites (but does not require) a Cartesian interpretation. Their suggestions about the time course of “editorial” revision of the multiple drafts and the possibility of restoration of the information in abandoned drafts are possible extensions of the Multiple Drafts Model.
Commercializing Clinical Trials — Risks and Benefits of the CRO Boom
Authors: Miriam Shuchman
Journal: New England Journal of Medicine (2007)

In a trend that has received surprisingly little attention, contract research organizations (CROs) have gradually taken over much of academia's traditional role in drug development over the past decade. They've been able to do so by offering greater speed and efficiency in conducting clinical trials than academic groups can, but questions have been raised about their qualifications, ethics, accountability, and degree of independence from their pharmaceutical-industry clients.Annual CRO-industry revenues have increased from about $7 billion in 2001 to an estimated $17.8 billion today; of more than 1000 CROs in operation, the four largest — Quintiles, Covance, Pharmaceutical Product Development . . .
Relative importance of SR load and cytoplasmic calcium concentration in the genesis of aftercontractions in cardiac myocytes
Authors: R Egdell
Journal: Cardiovascular Research (2000)

Objective: To determine whether calcium overload of the sarcoplasmic reticulum underlies drive train-induced aftercontractions in cardiac myocytes. Methods: Sarcoplasmic reticulum calcium contents were measured immediately prior to drive train-induced aftercontractions in isolated guinea pig cardiac myocytes, using caffeine application under voltage clamp conditions. Cell shortening during caffeine exposure and cell shortening during the final stimulated beat of the drive train and the delay between caffeine exposure and the onset of inward current were also used as indirect measures of sarcoplasmic reticulum load. Results: At the threshold for aftercontractions, all four measures of sarcoplasmic reticulum load showed interruption of the positive relationship between stimulation frequency and sarcoplasmic reticulum content, the sarcoplasmic reticulum being no more loaded prior to an aftercontraction than following subthreshold drive trains. Intracellular calcium concentration, estimated with the calcium-sensitive dye indo-1, was higher in cells showing aftercontractions than those not. Conclusions: We conclude that calcium overload of the sarcoplasmic reticulum does not underlie spontaneous calcium release in this situation and the primary trigger for spontaneous release may instead be raised cytoplasmic calcium concentration.
COLD BATHS; THEIR USE AND ABUSE.
Authors: JOHN D. THOMAS
Journal: JAMA (1896)

I do not intend to go into elaborate detail as to the history of the ablutions of man from the time Adam and Eve in their pristine bathing costumes, plunged into the cooling waters of Eden to the present era, when their descendants are carrying the rage for everything antique to the point of fashioning their bathing costumes as nearly as possible after those of their good old father and mother. Suffice it that the cold bath maintains its right to belong to the D.A.R. of therapeutics by tracing its ancestry back to the fountain head of medicine, Hippocrates. Musa, Galen, Paulus Ægineta, one of the Savonarolas, Van Helmont, Blair, Huxham, Floyer, Hoffman, the Hahns, Wright, Currie, Priessnitz, Fleury, Brand, Jurgensen, Winternitz, Baruch, thus runs the pedigree, long and distinguished enough to have it fare better in this generation; and certainly should procure a hearing for it from any collection
Methyl Chloroform Intoxication
Authors: Richard D. Stewart
Journal: JAMA (1971)

Methyl chloroform (1, 1, 1-trichloroethane) is a widely used solvent in the United States. Excessive absorption of this substance through the lungs or gastrointestinal tract produces central nervous system (CNS) depression proportional to the amount absorbed. Mild liver and kidney dysfunction may occur transiently following recovery from CNS depression. The diagnosis of exposure is established by specifically identifying the solvent in the expired breath. Serial breath analyses allow the estimation of the total amount absorbed. The treatment is supportive, to combat the effects of CNS depression. The principles of diagnosis and treatment are illustrated by four cases of accidental vapor exposure.
Osteonecrosis of the Jaw — Do Bisphosphonates Pose a Risk?
Authors: John P. Bilezikian
Journal: New England Journal of Medicine (2006)

Nitrogen-containing bisphosphonates are used widely for the management of metastatic cancer in bone (intravenous zoledronic acid or pamidronate), for the prevention and treatment of osteoporosis (oral alendronate, risedronate, and ibandronate and intravenous ibandronate), for the treatment of Paget's disease of bone (intravenous pamidronate and oral alendronate and risedronate), and for the short-term management of acute hypercalcemia (intravenous zoledronic acid and pamidronate). The nitrogen moiety attached to the side chain of the middle carbon of the phosphorus–carbon–phosphorus bisphosphonate backbone renders these drugs much more potent as inhibitors of bone resorption than the bisphosphonates that do not contain nitrogen (etidronate and clodronate). . . .
Sequential Trends in Overall and Cause-Specific Mortality in Diabetic and Nondiabetic Pima Indians
Authors: Maurice L Sievers, Robert G Nelson, Peter H Bennett
Journal: Diabetes Care (1996)

OBJECTIVE To compare sequential trends in overall and cause-specific death rates for diabetic and nondiabetic Pima Indians. RESEARCH DESIGN AND METHODS Underlying causes of death in Pimas aged 15 years old were determined for the years 1975–1989 from review of death certificates and medical records. Overall and cause-specific death rates were compared for consecutive intervals. RESULTS The all-causes death rate, age- and sex-adjusted, did not change significantly between the first and second halves of the study for diabetic (death rate ratio [DRR] = 0.99, 95% CI 0.70–1.4) or nondiabetic Pimas (DRR = 0.92, 95% CI 0.74–1.1). Among diabetic Pimas, however, the death rate for diabetic nephropathy declined from 2.7 to 1.5/1,000 person-years (DRR = 0.55, 95% CI 0.33–0.93), with ischemic heart disease (IHD) replacing diabetic nephropathy as the leading cause in the second half (DRR = 1.5, 95% CI 0.91–2.6). For diabetic and nondiabetic Pimas combined, the death rate in three consecutive 5-year periods declined progressively for alcoholic liver disease (P = 0.024) and external causes of death (P = 0.016), the largest component of which was automobile accidents. CONCLUSIONS The decrease in death rate for diabetic nephropathy may be a result of greater access to and improvements in renal replacement therapy. Because of shared risk factors, however, the IHD death rate increased and largely offset the decrease in diabetic nephropathy deaths. The decline in deaths from alcoholic liver disease and from automobile accidents parallels the national trend.
Role of Endogenous Neural Stem Cells in Spinal Cord Injury and Repair
Authors: Moa Stenudd, Hanna Sabelström, Jonas Frisén
Journal: JAMA Neurology (2014)

Spinal cord injury is followed by glial scar formation, which has positive and negative effects on recovery from the lesion. More than half of the astrocytes in the glial scar are generated by ependymal cells, the neural stem cells in the spinal cord. We recently demonstrated that the neural stem cell-derived scar component has several beneficial functions, including restricting tissue damage and neural loss after spinal cord injury. This finding identifies endogenous neural stem cells as a potential therapeutic target for treatment of spinal cord injury.
US president and Congress set to clash over stem cell research
Authors: Janice Hopkins Tanne
Journal: BMJ (2005)

The US House of Representatives passed a bill last week to increase funding for research on embryonic stem cells. The research would use frozen leftover embryos voluntarily donated by couples who no longer needed them for fertility treatment.

The move challenges President George Bush, who restricted federal funding for stem cell research to lines in existence before 9 August 2001. Scientists say that few lines from before this date remain, and they may be contaminated, limiting US research ( BMJ 2005;330: 214

The president, who has never used his veto before, has said that he would veto federal legislation to fund …
FATAL POST-TRANSFUSION REACTIONS
Authors: OSBORNE ALLEN BRINES
Journal: JAMA (1930)

One cannot help being impressed by the rare occurrence of death immediately following and directly attributable to blood transfusion. There have been two such accidents in 4,000 transfusions that I have performed, which constitutes a mortality of 0.05 per cent. In view of the uniformly beneficial results derived from transfusion, with which all physicians are familiar, the procedure frequently assuming the proportions of a miraculous life-saving operation, the mortality is insignificant and compares favorably with that caused by other forms of treatment. No intravenous procedure is entirely free from danger. The mortality following arsphenamine injection is nearly that which follows blood transfusion. When a blood transfusion is clearly indicated and necessary, as all surgical and medical treatment should be, the risk is negligible because the end justifies the means. Post-transfusion reactions may be classified as: (1) those due to incompatibility; (2) chemical reactions, and (3) allergic reactions. In this series
Hewlett Packard 95 LX Palmtop Computer
Authors: Peter G. Ruehlman
Journal: JAMA (1992)

Owing to recent trends with restrictive third-party payers, many physicians find themselves in the unfortunate position of commuting to several hospitals. This situation, combined with the exponential increase in medical knowledge, has created increasing logistical problems for many commuting physicians. The Hewlett Packard 95 LX palmtop computer has provided some partial solutions to this dilemma. Many electronic organizers currently exist on the market to allow quick access to appointments, telephone numbers, and calculator functions. The HP 95 LX palmtop computer, however, represents a major advance over such predecessors. Because it's a DOS-based instrument, entire files can be stored and downloaded from the personal computer via the optional Connectivity Pack. Furthermore, the HP palmtop computer also has an intriguing infrared port, which allows wireless communication between identical units. The unit is run on two AA batteries, weighs 11 ounces, and measures 6.3 × 3.4 × 1.0 inches. It fits nicely
Understanding H7N9 avian flu
Authors: C. Dai, M. Jiang
Journal: BMJ (2013)

The outbreak of H7N9 avian influenza in China had killed 17 people and infected 82 by 18 April 2013.1 Thirty one cases occurred in Shanghai city, 25 in Zhejiang province, 20 in Jiangsu province, three in Anhui province, two in Henan province, and one in Beijing city.

One child in Beijing, who displayed no symptoms and tested positive for the H7N9 virus, was considered a carrier and is being observed to see whether he developed symptoms. This child had been in contact with Beijing’s first confirmed case of H7N9. Beijing Health …
Hope, Suicide, and Medical Practice
Authors: Jerome A. Motto
Journal: JAMA (1975)

Beck and his colleagues, in this issue ofThe Journal(p 1146), point out that the degree of hopelessness experienced by a depressed patient provides a more accurate indication of suicide risk than does the severity of the patient's depression. The implication of this observation goes beyond the provision of a valuable and relatively simple aid to assessing suicide risk. It raises anew the issue of the role the physician plays in maintaining hope in those patients whose very survival may depend on it. In the not-so-distant past, before such advances as broad-spectrum antibiotics and open heart surgery, physicians were more often in the role of simply nurturing and maintaining hope, if only in "standing by" during a crisis. They were accorded much esteem for that even though they may have been forced into it by the lack of more specific therapeutic measures. Certainly there was a special message conveyed
New Orleans doctor is charged with giving lethal injections during floods
Authors: Fred Charatan
Journal: BMJ (2006)

A doctor and two nurses were arrested on 18 July and charged with giving four patients, aged 62 to 91, lethal injections of sedatives during the flooding of New Orleans last year.

The patients were in the long term care facility on the seventh floor of Memorial Medical Center, which had been cut off by flooding and was surrounded by nearly two metres of water, after hurricane Katrina hit New Orleans on 29 August 2005. The hospital was left without electric power, supplies, or functioning lifts. The temperature inside the hospital had risen to more than 38°C.

The doctor, an otorhinolaryngologist who volunteered her services at the hospital, told the Baton Rouge television station WBRZ in December 2005 that some patients had “do not resuscitate” (DNR) orders. The staff had to decide whether critically ill patients would survive the arduous evacuation through the environment of looting and anarchy that prevailed in New Orleans at the time.

A state affidavit said that the doctor made up a list of the sickest patients remaining in the hospital three days after the storm. The affidavit, which was released by the office of Louisiana’s state attorney general, Charles Foti, said that a decision had been made to administer lethal doses to those patients whose cases were deemed to be terminal.

Although the doctor and two nurses were not formally charged with a crime, their arrest warrant says that the three committed second degree murder, a crime that could result in a life sentence.

Court papers say that tissue samples taken from the dead patients at the hospital tested positive for morphine and midazolam, a benzodiazepine derivative, and that the amount of midazolam present was found to be higher than the usual treatment dose of less than 2.5 mg intravenously in a normal healthy adult. Medical records reviewed by investigators also showed that none of the four patients was taking either of the two drugs as part of their routine care.

Mr Foti plans to turn the information collected by his office over to the New Orleans district attorney, who will decide whether to ask a grand jury for a formal indictment.

Steven Miles, a professor of medicine at the University of Minnesota’s Center for Bioethics, said that instead of trying to kill it was more likely that the people charged were trying to relieve the patients’ pain “in a resource poor environment and were doing the best they could.”

Arthur Caplan, professor of bioethics and director of the Center for Bioethics at the University of Pennsylvania, said, “You’ve got, at best, mercy and panic, but that doesn’t add up to an excusable homicide.”
Pulmonary function after bone marrow transplantation for chronic myeloid leukaemia.
Authors: T G Sutedja, J F Apperley, J M Hughes, V R Aber, H G Kennedy, P Nunn, L Jones, L Hopper, J M Goldman
Journal: Thorax (1988)

Pulmonary function was measured before and at intervals after treatment in 44 patients who received a bone marrow transplant for chronic myeloid leukaemia in the chronic phase. All patients were treated with cytotoxic drugs, total body irradiation, and post-graft immunosuppression. Thirty four patients surviving for 12 months were followed at three monthly intervals and 16 patients for 24 months. Fifteen patients received unmanipulated donor marrow cells and 29 patients received donor marrow cells depleted of lymphocytes ex vivo with the monoclonal antibody Campath-1. The 21 patients treated early in this study received 10 Gy of total body irradiation whereas the 23 patients treated more recently, who were all T lymphocyte depleted, received 12 Gy. Pretransplant lung function for the group was normal and was similar in survivors (n = 34) and nonsurvivors (n = 10), and in smokers (n = 8) and non-smokers (n = 36). (Carbon monoxide transfer factor--TLCO) was under 75% of predicted normal in nine patients before transplantation. TLCO, carbon monoxide transfer coefficient (KCO), FEV1, and vital capacity (VC) values were lower 6 and 12 months after bone marrow transplant than initially. The greatest decline was in TLCO, from an initial value of 89% to 66% at 6 and 70% at 12 months. The 16 longer term survivors showed significant recovery of function between 6 and 24 months after bone marrow transplant for TLCO, KCO, and VC, the increase ranging from 6.3% to 7.3% predicted. Airflow obstruction (FEV1/VC ratio less than 70%) developed in one patient. The major factors associated with deterioration in pulmonary function at 6 and 12 months after transplantation in the 34 survivors (stepwise multiple regression analysis) were (a) transplantation with T cell depleted donor marrow (p less than 0.005) and higher total body irradiation dose (p less than 0.02) with a fall in KCO and an increase in the FEV1/VC ratio; (b) chronic graft versus host disease with a fall in VC (p less than 0.01); and less fall in KCO (p less than 0.01); and (c) acute graft versus host disease with a fall in FEV1 (p less than 0.01). It is considered that most patients who survive the short term risks of bone marrow transplant have only minor long term impairment of pulmonary function.