Survey of NAACLS accredited histotechnology programs in the United States.

Histotechnology educational programs are accredited by the National Accrediting Agency for Clinical Laboratory Sciences (NAACLS) and currently number fewer than 50 in the United States which contributes to the shortages of laboratory personnel. A survey tool designed with REDCap software was distributed to all programs identified on the NAACLS website and consisted of three parts: a) program information, b) facility information, and c) challenges. Programs are located primarily in large urban centers where populations are most concentrated. The median class size was 6 which may explain the excellent student outcomes to include 96% graduation rates and 90.7% board of registry examination pass rates. Overall, programs had ample equipment, funding, and administrative support. Costs to attend the programs were relatively low (<$3,000 per semester) for over half of the programs. However, due to the small number of accredited education programs across the US, potential students do not often have access to an institution in their area. The programs indicated that the most common challenge was recruitment of adequate high-quality candidates which may explain, in part, the persistent shortage of personnel in the histology laboratory.

First-in-human trial exploring safety, antitumor activity, and pharmacokinetics of Sym013, a recombinant pan-HER antibody mixture, in advanced epithelial malignancies.

PURPOSE: Sym013 contains six humanized monoclonal antibodies that bind to non-overlapping epitopes on three human epidermal growth factor receptors (HER1-3). Preclinical studies suggested Sym013 strongly suppresses growth of multiple epithelial tumors. This is a first-in-human study exploring safety and efficacy of Sym013 in patients with advanced epithelial malignancies. METHODS: Dose escalation used single-patient cohorts until the stopping rule was met, followed by 3 + 3 design. Dose levels planned were: 1, 2, 4, 6, 9, 12, 15, and 18 mg/kg. Treatment cycles were 28 days with imaging every eight weeks. Serum samples were collected at multiple time points for assessment of pharmacokinetics and development of anti-drug antibodies. RESULTS: Thirty-two patients were enrolled with multiple solid tumors, most common being colorectal cancer (CRC; 10/32, 31%). Due to mucositis, rash, and diarrhea at 4 mg/kg once-weekly, dosing was changed to biweekly (Q2W). Mandatory prophylaxis was added due to Grade 3 infusion-related reaction and oral mucositis at 9 mg/kg Q2W. The 15 mg/kg Q2W cohort was enrolling when the study was terminated for business reasons. Most common adverse events were skin (81%) and gastrointestinal (75%) disorders, including dermatitis/rash, stomatitis, and diarrhea. One patient with CRC achieved a partial response; 12 patients with varied malignancies had stable disease. CONCLUSION: During the conduct of the study, management of frequent infusion-related reactions, skin toxicities, and mucosal disorders, which are indicative of HER inhibition, necessitated multiple protocol amendments. The investigators, in concert with the Sponsor, agreed that achieving a tolerated regimen with acceptable target saturation was unlikely. TRIAL REGISTRY: www. CLINICALTRIALS: gov ; NCT02906670 (September 20, 2016).

Role of environment and sex differences in the development of autoimmune diseases: a roundtable meeting report.

Autoimmune diseases (ADs) impose substantial health and financial burdens in the United States and in many parts of the world. Women are disproportionately affected by many of these disorders, which often contribute to lifelong disabilities. While the number of patients with some ADs appears to be rising, the complexities of conducting epidemiological studies prevent a thorough understanding of the prevalence and incidence of these various conditions. Research on environmental influences of these illnesses is limited, although they are generally hypothesized to result from the interaction of environmental agents in genetically susceptible individuals. Further, there is little known regarding the role of sex and gender in the environmentally influenced mechanisms leading to the development of AD. To address these issues, particularly the roles of environment and sex and gender in ADs and the factors that contribute to the rise in ADs, the Society for Women's Health Research convened an interdisciplinary roundtable of experts from academia, medicine, and government agencies to share their expertise, address knowledge gaps in research, and propose future research recommendations.

Hormonal modulation of two coordinated rhythmic motor patterns.

Neuromodulation is well known to provide plasticity in pattern generating circuits, but few details are available concerning modulation of motor pattern coordination. We are using the crustacean stomatogastric nervous system to examine how co-expressed rhythms are modulated to regulate frequency and maintain coordination. The system produces two related motor patterns, the gastric mill rhythm that regulates protraction and retraction of the teeth and the pyloric rhythm that filters food. These rhythms have different frequencies and are controlled by distinct mechanisms, but each circuit influences the rhythm frequency of the other via identified synaptic pathways. A projection neuron, MCN1, activates distinct versions of the rhythms, and we show that hormonal dopamine concentrations modulate the MCN1 elicited rhythm frequencies. Gastric mill circuit interactions with the pyloric circuit lead to changes in pyloric rhythm frequency that depend on gastric mill rhythm phase. Dopamine increases pyloric frequency during the gastric mill rhythm retraction phase. Higher gastric mill rhythm frequencies are associated with higher pyloric rhythm frequencies during retraction. However, dopamine slows the gastric mill rhythm frequency despite the increase in pyloric frequency. Dopamine reduces pyloric circuit influences on the gastric mill rhythm and upregulates activity in a gastric mill neuron, DG. Strengthened DG activity slows the gastric mill rhythm frequency and effectively reduces pyloric circuit influences, thus changing the frequency relationship between the rhythms. Overall dopamine shifts dependence of frequency regulation from intercircuit interactions to increased reliance on intracircuit mechanisms.

Drug-associated psychoses and criminal responsibility.

At present, the law draws a distinction when assigning criminal responsibility to those who commit offences while experiencing psychotic symptoms: if the symptoms are believed to arise because of ingesting drugs (an external cause), the offender is generally convicted of the offence; if the symptoms arise from a mental illness (an internal cause), the offender may be afforded a defence of insanity. In practice, drawing such a distinction can be problematic. There are difficulties for example in determining criminal responsibility when the use of drugs is followed by the emergence of a psychotic illness process that then continues to have an independent existence even in the absence of the ongoing substance use. This article analyses legal, policy, and expert witness perspectives relating to liberal, conservative, and intermediate approaches to this problematic area of jurisprudence.

Divergent co-transmitter actions underlie motor pattern activation by a modulatory projection neuron.

Co-transmission is a common means of neuronal communication, but its consequences for neuronal signaling within a defined neuronal circuit remain unknown in most systems. We are addressing this issue in the crab stomatogastric nervous system by characterizing how the identified modulatory commissural neuron (MCN)1 uses its co-transmitters to activate the gastric mill (chewing) rhythm in the stomatogastric ganglion (STG). MCN1 contains gamma-aminobutyric acid (GABA) plus the peptides proctolin and Cancer borealis tachykinin-related peptide Ia (CabTRP Ia), which it co-releases during the retractor phase of the gastric mill rhythm to influence both retractor and protractor neurons. By focally applying each MCN1 co-transmitter and pharmacologically manipulating each co-transmitter action during MCN1 stimulation, we found that MCN1 has divergent co-transmitter actions on the gastric mill central pattern generator (CPG), which includes the neurons lateral gastric (LG) and interneuron 1 (Int1), plus the STG terminals of MCN1 (MCN1(STG)). MCN1 used only CabTRP Ia to influence LG, while it used only GABA to influence Int1 and the contralateral MCN1(STG). These MCN1 actions caused a slow excitation of LG, a fast excitation of Int1 and a fast inhibition of MCN1(STG). MCN1-released proctolin had no direct influence on the gastric mill CPG, although it likely indirectly regulates this CPG via its influence on the pyloric rhythm. MCN1 appeared to have no ionotropic actions on the gastric mill follower motor neurons, but it did use proctolin and/or CabTRP Ia to excite them. Thus, a modulatory projection neuron can elicit rhythmic motor activity by using distinct co-transmitters, with different time courses of action, to simultaneously influence different CPG neurons.

Erlotinib plus gemcitabine in patients with unresectable pancreatic cancer and other solid tumors: phase IB trial.

PURPOSE: The purpose of this phase IB trial was to evaluate the tolerability, pharmacokinetics and preliminary evidence of antitumor activity of erlotinib plus gemcitabine in patients with pancreatic cancer and other solid tumors. PATIENTS AND METHODS: Patients included those with advanced pancreatic adenocarcinoma or other malignancies potentially responsive to gemcitabine. In the escalating phase of the trial, patients were enrolled in sequential cohorts using 100 or 150 mg oral daily dosing of erlotinib. Gemcitabine dose was 1,000 mg/m(2) weekly x 7 (first cycle), then weekly x 3, every 4 weeks. RESULTS: Twenty-six patients completed at least one course on study. In Cohort IA, at the 100 mg/day dose of erlotinib, three patients have developed grade 3 transaminase elevations. After stricter inclusion criteria were adopted (Cohort IB), no additional events of grade 3 transaminase elevations were observed and the dose of erlotinib was escalated to 150 mg/day (Cohorts IB and IIB) without reaching dose-limiting toxicities. The most common toxicities included diarrhea, skin rash, fatigue and neutropenia. The pharmacokinetic analyses did not reveal any significant interactions between erlotinib and gemcitabine. Objective responses were seen in two patients: cholangiocarcinoma and pancreatic cancer. Patients with unresectable or metastatic pancreatic cancer (n = 15) had a median progression-free survival of 289 days, the estimated overall survival of 389 days (12.5 months), and a 1-year survival rate of 51%. CONCLUSION: The 150 mg/day dose of erlotinib can be safely administered in combination with standard dose gemcitabine in selected patients with pancreatic cancer and other advanced solid tumors. Promising antitumor activity has been observed in patients with pancreatic cancer.

Phase I, pharmacokinetic, and biological study of erlotinib in combination with paclitaxel and carboplatin in patients with advanced solid tumors.

PURPOSE: To assess the feasibility of administering erlotinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, in combination with paclitaxel and carboplatin, and to identify pharmacokinetic interactions, evaluate downstream effects of EGFR inhibition on surrogate tissues, and seek preliminary evidence for clinical activity. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated continuously with erlotinib at doses of 100, 125, and 150 mg/d orally along with fixed i.v. doses of paclitaxel 225 mg/m(2) and carboplatin AUC 6 mg x min/mL, both on day 1 every 3 weeks. RESULTS: Twenty evaluable patients were treated with 136 courses of erlotinib, paclitaxel, and carboplatin. Myelosuppression, skin rash, and diarrhea were the principal toxicities. Dose limiting diarrhea occurred in 1 of 6 patients at the 100 mg erlotinib dose level, whereas 0 of 9 evaluable patients at the 125 mg erlotinib dose level experienced dose limiting toxicity and 3 of 5 evaluable patients at 150 mg erlotinib experienced dose limiting skin rash and neutropenic sepsis. There was no evidence of pharmacokinetic interactions between paclitaxel and erlotinib; however, total carboplatin exposure trended higher in the presence of erlotinib. No consistent downstream effects on EGFR inhibition were found in skin. Durable objective responses were observed in non-small-cell lung and head and neck cancers. CONCLUSIONS: A dose level of erlotinib 125 mg combined with paclitaxel 225 mg/m(2) and carboplatin AUC 6 mg.min/mL is recommended for disease-directed studies. This phase I trial was followed by a randomized phase III study in non-small-cell lung cancer using a similar regimen.

Intercircuit control via rhythmic regulation of projection neuron activity.

Synaptic feedback from rhythmically active neuronal circuits commonly causes their descending inputs to exhibit the rhythmic activity pattern generated by that circuit. In most cases, however, the function of this rhythmic feedback is unknown. In fact, generally these inputs can still activate the target circuit when driven in a tonic activity pattern. We are using the crab stomatogastric nervous system (STNS) to test the hypothesis that the neuronal circuit-mediated rhythmic activity pattern in projection neurons contributes to intercircuit regulation. The crab STNS contains an identified projection neuron, modulatory commissural neuron 1 (MCN1), whose tonic stimulation activates and modulates the gastric mill (chewing) and pyloric (filtering of chewed food) motor circuits in the stomatogastric ganglion (STG). During tonic stimulation of MCN1, the pyloric circuit regulates both gastric mill cycle frequency and gastropyloric coordination via a direct synapse onto a gastric mill neuron in the STG. However, when MCN1 is spontaneously active, it has a pyloric-timed activity pattern attributable to synaptic input from the pyloric circuit. This pyloric-timed activity in MCN1 provides the pyloric circuit with a second pathway for regulating the gastric mill rhythm. At these times, the direct STG synapse from the pyloric circuit to the gastric mill circuit is not necessary for pyloric regulation of the gastric mill rhythm. However, in the intact system, these two pathways play complementary roles in this intercircuit regulation. Thus, one role for rhythmicity in modulatory projection neurons is to enable them to mediate the interactions between distinct but related neuronal circuits.