Pulmonary squamous cell carcinoma with a lepidic-pagetoid growth pattern.

We report a rare case of a peripheral squamous cell carcinoma (SCC) of the lung in which most of the tumor displayed a "lepidic" growth pattern. The tumor cells also appeared to grow along the alveolar walls between the overlying pneumocytes and underlying basement membrane, a form reminiscent of the "pagetoid" mode of spread. The neoplastic cells were positive for the squamous markers p63 and p40.

An experimental test of the effects of redacting grant applicant identifiers on peer review outcomes.

Background: Blinding reviewers to applicant identity has been proposed to reduce bias in peer review.

Methods: This experimental test used 1200 NIH grant applications, 400 from Black investigators, 400 matched applications from White investigators, and 400 randomly selected applications from White investigators. Applications were reviewed by mail in standard and redacted formats.

NIH peer review: Criterion scores completely account for racial disparities in overall impact scores.

Previous research has found that funding disparities are driven by applications' final impact scores and that only a portion of the black/white funding gap can be explained by bibliometrics and topic choice. Using National Institutes of Health R01 applications for council years 2014-2016, we examine assigned reviewers' preliminary overall impact and criterion scores to evaluate whether racial disparities in impact scores can be explained by application and applicant characteristics. We hypothesize that differences in commensuration-the process of combining criterion scores into overall impact scores-disadvantage black applicants.

Scientific productivity: An exploratory study of metrics and incentives.

Competitive pressure to maximize the current bibliometric measures of productivity is jeopardizing the integrity of the scientific literature. Efforts are underway to address the 'reproducibility crisis' by encouraging the use of more rigorous, confirmatory methods. However, as long as productivity continues to be defined by the number of discoveries scientists publish, the impact factor of the journals they publish in and the number of times their papers are cited, they will be reluctant to accept high quality methods and consistently conduct and publish confirmatory/replication studies.

NIH Peer Review: Scored Review Criteria and Overall Impact.

The National Institutes of Health (NIH) is the largest source of funding for biomedical research in the world. Funding decisions are made largely based on the outcome of a peer review process that is intended to provide a fair, equitable, timely, and unbiased review of the quality, scientific merit, and potential impact of the research. There have been concerns about the criteria reviewers are using, and recent changes in review procedures at the NIH now make it possible to conduct an analysis of how reviewers evaluate applications for funding.

Examining the Predictive Validity of NIH Peer Review Scores.

The predictive validity of peer review at the National Institutes of Health (NIH) has not yet been demonstrated empirically. It might be assumed that the most efficient and expedient test of the predictive validity of NIH peer review would be an examination of the correlation between percentile scores from peer review and bibliometric indices of the publications produced from funded projects. The present study used a large dataset to examine the rationale for such a study, to determine if it would satisfy the requirements for a test of predictive validity.

Scopolamine induced deficits in a battery of rat cognitive tests: comparisons of sensitivity and specificity.

Despite much research, the cognitive effects of scopolamine hydrobromide, a cholinergic antagonist, remain controversial. Scopolamine affects multiple systems each of which can impact behavior. One way to tease apart the effects of the drug is to determine the effects of low scopolamine doses on different abilities.

Clinical attrition due to biased preclinical assessments of potential efficacy.

Unless it is carefully controlled, bias often distorts the results of clinical trials, usually exaggerating the magnitude of true efficacy. For that reason, procedures to limit bias have been mandated by the FDA when assessing efficacy in clinical trials. The present review shows that the effects of bias in preclinical studies are at least as large as in clinical trials, and since bias is not usually controlled in preclinical proof of concept studies, compounds that actually have little or no therapeutic potential may often be advanced into clinical trials.

Donepezil primarily attenuates scopolamine-induced deficits in psychomotor function, with moderate effects on simple conditioning and attention, and small effects on working memory and spatial mapping.

Rationale: Alzheimer's dementia (AD) patients have profound deficits in cognitive and social functions, mediated in part by a decline in cholinergic function. Acetylcholinesterase inhibitors (AChEI) are the most commonly prescribed treatment for the cognitive deficits in AD patients, but their therapeutic effects are small, and it is still not clear if they primarily affect attention, memory, or some other cognitive/behavioral functions.

Objectives: The objective of the present experiments was to explore the effects of donepezil (Aricepttrade mark), an AChEI, on behavioral deficits related exclusively to cholinergic dysfunction.

Soluble Abeta and cognitive function in aged F-344 rats and Tg2576 mice.

Recent findings suggest that Alzheimer's dementia may be mediated by soluble beta amyloid (Abeta) more than the deposits of aggregated, insoluble Abeta, and vulnerability to cognitive deficits after scopolamine challenge may help identify AD even in patients that are still pre-symptomatic. The objectives of the present experiments were to determine if vulnerability to cognitive deficits after scopolamine challenge is related to levels of soluble Abeta, and if levels of soluble Abeta are more closely related to cognitive deficits than levels of insoluble Abeta, even in aged, transgenic mice, after they have developed very high levels of insoluble Abeta. Aged F-344 rats and young mice over-expressing the Swedish mutation in the human amyloid precursor protein (APPsw; Tg2576+) had elevated levels of soluble Abeta, and were more vulnerable to scopolamine challenge in the Morris water maze (MWM), relative to young rats and Tg2576- mice; but, among individual animals, higher levels of soluble Abeta were not correlated with vulnerability to scopolamine.

Adverse effects of gabapentin and lack of anti-allodynic efficacy of amitriptyline in the streptozotocin model of painful diabetic neuropathy.

Amitriptyline and gabapentin are the primary treatments for painful diabetic neuropathy (PDN), and it is clear that they produce beneficial effects, but there are questions about these treatments that have not been adequately addressed. For example, although there is a growing consensus that the therapeutic effects of amitriptyline in pain patients are independent of its effects on mood, it is not clear that amitriptyline has specific and direct effects on pain. There is also a fairly broad consensus that gabapentin is safe and well tolerated, but the side-effect profile of gabapentin has not been adequately assessed in pain populations.

The pharmacology of DMP696 and DMP904, non-peptidergic CRF1 receptor antagonists.

CRF(1) antagonists DMP696 and DMP904 were designed as drug development candidates for the treatment of anxiety and depression. Both compounds display nanomolar affinity for human CRF(1) receptors, and exhibit >1000-fold selectivity for CRF(1) over CRF(2) receptors and over a broad panel of other proteins. DMP696 and DMP904 block CRF-stimulated adenylyl cyclase activity in cortical homogenates and cell-lines expressing CRF(1) receptors.

Effects of CRF1 receptor antagonists and benzodiazepines in the Morris water maze and delayed non-matching to position tests.

Rationale: Benzodiazepines continue to be widely used for the treatment of anxiety, but it is well known that benzodiazepines have undesirable side effects, including sedation, ataxia, cognitive deficits and the risk of addiction and abuse. CRF(1) receptor antagonists are being developed as potential novel anxiolytics, but while CRF(1) receptor antagonists seem to have a better side-effect profile than benzodiazepines with respect to sedation and ataxia, the effects of CRF(1) receptor antagonists on cognitive function have not been well characterized. It is somewhat surprising that the potential cognitive effects of CRF(1) receptor antagonists have not been more fully characterized since there is some evidence to suggest that these compounds may impair cognitive function.

Long-lasting functional disabilities in middle-aged rats with small cerebral infarcts.

Recommendations from experts and recently established guidelines on how to improve the face and predictive validity of animal models of stroke have stressed the importance of using older animals and long-term behavioral-functional endpoints rather than relying almost exclusively on acute measures of infarct volume in young animals. The objective of the present study was to determine whether we could produce occlusions in older rats with an acceptable mortality rate and then detect reliable, long-lasting functional deficits. A reversible intraluminar suture middle cerebral artery occlusion (MCAO) procedure was used to produce small infarcts in middle-aged rats.

Analgesic effects of adrenal chromaffin allografts: contingent on special procedures or due to experimenter bias?

Many articles have reported that adrenal chromaffin cell transplants produce analgesic effects. Surprisingly, studies conducted in our laboratory failed to detect analgesic effects of adrenal chromaffin cell transplants. Although we have attempted to replicate the procedures reported to produce analgesic effects with adrenal chromaffin transplants, many of the different cell preparation procedures we have examined are fairly complex, and it is possible that our transplants were not sufficiently viable because of some subtle difference in our cell preparation procedures.

An assessment of the effects of serotonin 6 (5-HT6) receptor antagonists in rodent models of learning.

Antagonists of serotonin 6 (5-HT6) receptors have been reported to enhance cognition in animal models of learning, although this finding has not been universal. We have assessed the therapeutic potential of the specific 5-HT6 receptor antagonists 4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide (Ro 04-6790) and 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046) in rodent models of cognitive function. Although mice express the 5-HT6 receptor and the function of this receptor has been investigated in mice, all reports of activity with 5-HT6 receptor antagonists have used rat models.

No detectable analgesic effects in the formalin test even with one million bovine adrenal chromaffin cells.

The present experiments were conducted to identify analgesic agents for transfection into immortalized adrenal chromaffin cell lines to maximize their analgesic potential. Analgesic agents known to be produced by adrenal chromaffin cells were infused intrathecally at a low dose (0.2 microg) which might conceivably be attained by adrenal chromaffin cell transplants.

Numerous adrenal chromaffin cell preparations fail to produce analgesic effects in the formalin test or in tests of acute pain even with nicotine stimulation.

Previous studies have reported that intrathecal implants of a variety of adrenal chromaffin cell preparations all produce analgesic effects in rodents. The major objective of the present study was to determine if any adrenal chromaffin cell preparations produce more robust analgesic effects than other cell preparations. The present study included adult rat adrenal chromaffin tissue allografts, purified adult bovine chromaffin cells, and polymer-encapsulated calf adrenal chromaffin cells, all prepared according to previously published procedures, as well as purified calf adrenal chromaffin cells.