Low-grade fibromatosis-like spindle cell carcinoma is a rare tumor in the breast, and represents a variant of the very heterogeneous group of metaplastic carcinomas of the breast. These tumors ...warrant distinction because of their resemblance to pure fibromatosis, their propensity for local recurrence, and their favorable prognosis among the metaplastic carcinomas of the breast. The diagnosis is potentially challenging, particularly on core needle biopsies, because of the morphologic overlap with other low-grade spindle cell lesions. Recognition of a proliferation of cytologically bland spindle cells with areas of epithelial differentiation in combination with immunohistochemistry using antibodies against cytokeratins and myoepithelial markers should aid in producing a definitive diagnosis. These tumors can be locally aggressive with an increased incidence of local recurrence, but the potential for lymph node or distant metastasis is low. Complete excision with adequate margins is considered curative in the majority of cases.
In the wake of the SARS-CoV-2 (COVID-19) pandemic, mental health has become a pivotal topic of discussion nationwide.1,2 Recognition of mental health disorders, mitigation of psychological distress ...during times of uncertainty, and abating negative stigma have become a focus of many groups, both internal and external to the medical field. Still, one of the most devastating sequelae of mental health afflictions is suicide.A retrospective review of all cases classified as suicide from January 2019 through December 2021 was conducted using the laboratory information system database within the Southwestern Institute of Forensic Sciences, the county division that performs postmortem examinations of cases under the jurisdiction of Dallas County and some surrounding North Texas counties. A total of 846 cases were retrieved that occurred within Dallas County. This cohort consisted of 659 men and 187 women with an average age of 42.9 years (median, 40 years). This study highlights compelling trends of suicides within a localized portion of North Texas during a 3-year period in which the population endured momentous and unprecedented worldwide events.
Acetyl fentanyl is a Schedule I controlled synthetic opioid that is becoming an increasingly detected “designer drug.” Routine drug screening procedures in local forensic toxicology laboratories ...identified a total of 41 overdose deaths associated with acetyl fentanyl within multiple counties of the southwestern region of the state of Pennsylvania. The range, median, mean, and standard deviation of blood acetyl fentanyl concentrations for these 41 cases were 0.13–2100 ng/mL, 11 ng/mL, 169.3 ng/mL, and 405.3 ng/mL, respectively. Thirty‐six individuals (88%) had a confirmed history of substance abuse, and all but one case (96%) were ruled multiple drug toxicities. This report characterizes this localized trend of overdose deaths associated with acetyl fentanyl and provides further evidence supporting an alarmingly concentrated opiate and opioid epidemic of both traditional and novel drugs within this region of the United States.
The p38 MAPK cascade is a key signaling pathway linked to a multitude of physiological functions and of central importance in inflammatory and autoimmune diseases. Although studied extensively, ...little is known about how conformation-specific inhibitors alter signaling outcomes. Here, we have explored the highly dynamic back pocket of p38 MAPK with allosteric urea fragments. However, screening against known off-targets showed that these fragments maintained the selectivity issues of their parent compound BIRB-796, while combination with the hinge-binding motif of VPC-00628 greatly enhanced inhibitor selectivity. Further efforts focused therefore on the exploration of the αC-out pocket of p38 MAPK, yielding compound 137 as a highly selective type-II inhibitor. Even though 137 is structurally related to a recent p38 type-II chemical probe, SR-318, the data presented here provide valuable insights into back-pocket interactions that are not addressed in SR-318 and it provides an alternative chemical tool with good cellular activity targeting also the p38 back pocket.
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•Selectivity analysis of allosteric urea fragments by differential scanning fluorimetry.•Design of selective p38 MAPK inhibitors by targeting folded P-loop conformations.•Potent and selective p38 type-II inhibitor 137 with good cellular activity.
A transparent corrections process is essential to assist in the maintenance of public confidence in scientific and medical research. In the era of preprints, fast-paced peer review, and early-access ...publication, errors and oversights from both authors and editors might be more common. The swift and open correction of the public record requires the participation of authors, journal editors, and publishers, and in this Viewpoint we share
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ESMO Congress 2023 Dwyer, Jessica E
The lancet oncology,
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Journal Article
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Adjuvant pembrolizumab in NSCLC Jonathan D Spicer (McGill University Health Centre, Montreal, QC, Canda) presented the second interim analysis results of KEYNOTE-671, a phase 3 trial, in which ...patients with resectable stage II, IIIA, or IIIB2 non-small-cell lung cancer (NSCLC) were randomly assigned (1:1) to receive neoadjuvant pembrolizumab (200 mg) plus cisplatin-based chemotherapy followed by resection and adjuvant pembrolizumab (n=397), or placebo plus chemotherapy plus adjuvant placebo following resection (n=400). Patients received either 10 mg (n=100) or 100 mg (n=88) of tarlatamab once every 2 weeks, and after a median follow up of 10·6 months, the primary endpoint of objective response rate (ORR) in the 10 mg group was 40·0% (97·5% CI 29·1–51·7) and in the 100 mg group was 31·8% (21·1–41·1). Dual mAbs for cervical cancer Jung-Yun Lee (Severance Hospital Yonsei University Health System, Seoul, South Korea) presented primary analysis results of AdvanTIG-202, a randomised, open-label, phase 2 trial that investigated use of tislelizumab plus ociperlimab versus tislelizumab monotherapy in patients with previously treated recurrent or metastatic cervical cancer who were not amenable to curative treatment. Among 19 patients who underwent treatment and surgery without delays, the primary endpoint of pathological response rate was 100%, with 79% showing complete response.
Alcohol ketoacidosis is a frequently missed diagnosis, but is well described in the literature. We present a case of ketoacidosis, likely alcohol ketoacidosis, in a 40 y-old chronic alcoholic ...patient. The detection of trace serum isopropanol prompted a discussion of alcohol ketoacidosis versus toxic isopropanol ingestion or a combination of both, including comparisons with citations in current literature.
The automated instruments used to analyze the patient's urine, blood, and serum samples are described.
The initial impression was severe metabolic acidosis with an increased anion gap and normal serum glucose and whole blood lactate. Testing for potential toxic ingestions detected only increased serum acetone and trace serum isopropanol. A urinalysis positive for ketones and an increased serum β-hydroxybutyrate concentration clenched the diagnosis of ketoacidosis.
Ketoacidosis with an increased anion gap in the absence of hyperglycemia or glycosuria in a chronic alcoholic patient should prompt the evaluation for alcohol ketoacidosis. Trace serum isopropanol may be worrisome for a toxic ingestion, but this finding in severe ketoacidosis may be explained by the reversible action of the enzyme alcohol dehydrogenase. Markedly increased serum isopropanol with a low serum acetone:isopropanol ratio would be more indicative of a toxic isopropanol ingestion.
Motorcycles make up 81 % of the total vehicle population and 74 % of road traffic deaths in Lao PDR. Helmets reduce the risk and severity of injuries resulting from motorcycle accidents by 72 %. ...Although Lao law mandates motorcycle helmet use among drivers and passengers, the prevalence of helmet use in Luang Prabang, Lao PDR is unknown. This project aimed to measure the prevalence of motorcycle helmet use among riders (i.e., drivers and passengers) in Luang Prabang.
An observational survey in Luang Prabang was conducted in February 2015 to measure the prevalence of motorcycle helmet use among drivers and passengers. Additionally, non-helmet wearing riders were surveyed to identify the reasons for helmet non-use.
Of 1632 motorcycle riders observed, only 16.2 % wore helmets. Approximately 29 % of adults wore helmets while less than 1 % of all children wore helmets. When surveyed about attitudes towards helmet use, the majority of adult drivers indicated that they did not like how adult helmets feel or made them look. Additionally, almost half of motorcyclists who did not own child helmets reported that their child was too young to wear a helmet.
Our finding that children wear helmets at significantly lower rates compared to adults is consistent with findings from neighboring countries in Southeast Asia. Results of this study have implications for public health campaigns targeting helmet use, especially among children.
Microwave-assisted Suzuki-Miyaura cross-coupling reactions have been employed towards the synthesis of three different MAPKAPK2 (MK2) inhibitors to study accelerated aging in Werner syndrome (WS) ...cells, including the cross-coupling of a 2-chloroquinoline with a 3-pyridinylboronic acid, the coupling of an aryl bromide with an indolylboronic acid and the reaction of a 3-amino-4-bromopyrazole with 4-carbamoylphenylboronic acid. In all of these processes, the Suzuki-Miyaura reaction was fast and relatively efficient using a palladium catalyst under microwave irradiation. The process was incorporated into a rapid 3-step microwave-assisted method for the synthesis of a MK2 inhibitor involving 3-aminopyrazole formation, pyrazole C-4 bromination using N-bromosuccinimide (NBS), and Suzuki-Miyaura cross-coupling of the pyrazolyl bromide with 4-carbamoylphenylboronic acid to give the target 4-arylpyrazole in 35% overall yield, suitable for study in WS cells.
Microwave-assisted synthesis of the pyrazolyl ketone p38 MAPK inhibitor RO3201195 in 7 steps and 15% overall yield, and the comparison of its effect upon the proliferation of Werner Syndrome cells ...with a library of pyrazolyl ketones, strengthens the evidence that p38 MAPK inhibition plays a critical role in modulating premature cellular senescence in this progeroid syndrome and the reversal of accelerated ageing observed in vitro on treatment with SB203580.
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