Purpose EGFR genotyping is now standard in the management of advanced lung adenocarcinoma, as this biomarker predicts marked benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 19 insertions are a poorly described family of EGFR mutations, and their association with EGFR TKI-sensitivity in lung adenocarcinoma is uncertain. Experimental Design Patients with lung cancers harboring EGFR exon 19 insertions were studied. The predicted effects of the insertions on the structure of the EGFR protein were examined, and EGFR exon 19 insertions were introduced into Ba/F3 cells to assess oncogenicity and in vitro sensitivity to EGFR TKIs. In patients receiving TKI, response magnitude was assessed with serial computed tomography (CT) measurement. Results Twelve tumors harboring EGFR exon 19 insertions were identified; patients were predominately female (92%) and never-smokers (75%). The 11 specimens available for full sequencing all demonstrated an 18 bp insertion that resulted in the substitution of a Pro for Leu at residue 747. The mutant EGFR transformed the Ba/F3 cells, which were then sensitive to EGFR TKI. Six patients with measurable disease received TKI and 5 had a response on serial CT. Conclusions EGFR exon 19 insertions are a newly appreciated family of EGFR TKI-sensitizing mutations, and patients with tumors harboring these mutations should be treated with EGFR-TKI. While these mutations may be missed through the use of some mutation-specific assays, the addition of PCR product size analysis to multi-gene assays allows sensitive detection of both exon 19 insertion and deletion mutations.

Peroxisome proliferator-activated receptors (PPAR) are novel nuclear receptors and PPARgamma ligands have been shown to produce pro-apoptotic effects in many cancer cell types, including colon cancer. PPARgamma ligands exert their effect through PPARgamma-dependent (genomic) and PPARgamma-independent (non-genomic) mechanisms. Recent evidence suggests that PPARgamma ligands exert their pro-apoptotic effects in part by directly antagonizing the NF-kappabeta pathway as well as through activation of the MAP kinase pathway. In this report, we have demonstrated that ciglitazone, a member of the thiazoldinedione class of PPARgamma ligands induces HT-29 colon cancer cells to undergo apoptosis and prior to apoptosis, ciglitazone exposure results in a transient phosphorylation of PPARgamma. This phosphorylation of PPARgamma was mediated through the ciglitazone-induced activation of Erk1/2. PPARgamma phosphorylation affected the genomic pathway by being inhibitory to PPARgamma-DNA binding and PPRE transcriptional activity, as well as the non-genomic pathway by increasing the physical interaction of PPARgamma with p65, leading to the inhibition of NF-kappabeta. Ciglitazone induced phosphorylation of PPARgamma through the MAP kinase pathway provides a potential regulatory mechanism for PPARgamma's physical interaction with p65, leading to inhibition of NF-kappabeta and subsequent apoptosis.

Background SARS-CoV-2 infection appears to increase the risk of adverse pregnancy outcomes such as preeclampsia in pregnant women. The mechanism(s) by which this occurs remains unclear. Methods We investigated the pathophysiology of SARS-CoV-2 at maternal-fetal interface in pregnant women who tested positive for the virus using RNA in situ hybridization (viral RNA), immunohistochemistry, and hematoxylin and eosin staining. To investigate whether viral infection alters the renin angiotensin system (RAS) in placenta which controls blood pressure, we treated human trophoblasts with recombinant Spike protein or a live modified virus with a vesicular stomatitis viral backbone expressing Spike protein (VSV-S). Findings Viral colonization was highest in maternal decidua, fetal trophoblasts, Hofbauer cells, and in placentas delivered prematurely. We localized SARS-CoV-2 to cells expressing Angiotensin-converting enzyme 2 (ACE2), and demonstrate that infected placentas had significantly reduced ACE2. In response to both Spike protein and VSV-S, cellular ACE2 decreased while Angiotensin II receptor type 1 (AT 1 R) increased with concomitant increase in soluble fms-like tyrosine kinase-1(sFlt1). Viral infection decreased pro-angiogenic factors, AT 2 R and Placental growth factor, which competitively binds to sFlt1. Sera from infected pregnant women had elevated levels of sFlt1 and Angiotensin II type 1-Receptor Autoantibodies prior to delivery, both signatory markers of preeclampsia. Conclusions SARS-CoV-2 colonizes ACE2-expressing maternal and fetal cells in the placenta. Infection in pregnant women correlates with alteration of placental RAS. As RAS regulates blood pressure, SARS-CoV-2 infection may thus increase adverse hemodynamic outcomes such as preeclampsia in pregnant women. Funding NIH/NICHD grants R01 HD091218 and 3R01HD091218-04S1 (RADx-UP Supplement)

Sleep disordered breathing (SDB) represents a spectrum of disorders, including habitual snoring and obstructive sleep apnea (OSA). Sleep disordered breathing is characterized by chronic intermittent hypoxia, airflow limitation, and recurrent arousals, which may lead to tissue hypoperfusion, hypoxia, and inflammation. In this study, we aimed to examine whether SDB during pregnancy was associated with histopathologic evidence of chronic placental hypoxia and/or uteroplacental underperfusion. The placentas of women with OSA (n  =  23) and habitual snoring (n  =  78) as well as nonsnorer controls (n  =  47) were assessed for histopathologic and immunohistochemical markers of chronic hypoxia and uteroplacental underperfusion. Fetal normoblastemia was significantly more prevalent in SDB placentas than in those of nonsnorer controls (34.6% and 56.5% in snorers and OSA, respectively, versus 6.4% in controls). Expression of the tissue hypoxia marker carbonic anhydrase IX (CAIX) was more common in OSA placentas than controls (81.5% and 91.3% in snorers and OSA, respectively, versus 57.5% in controls). Adjusting for confounders such as body mass index, diabetes mellitus, or chronic hypertension did not alter the results. The uteroplacental underperfusion scores were similar among the 3 groups. Our findings suggest that SDB during pregnancy is associated with fetoplacental hypoxia, as manifested by fetal normoblastemia and increased placental carbonic anhydrase IX immunoreactivity. The clinical implications and underlying mechanisms remain to be determined.

No abstract

The overprescription and improper use of antibiotics have contributed to the evolution of bacterial resistance, making it urgent to develop alternative therapies and agents with better efficacy as well as less toxicity to combat bacterial infections and keep new resistance from developing. In this work, a novel light-activable nano-antibiotic platform (TC-PCM@GNC-PND) was constructed by the incorporation of gold nanocages (GNC) and two thermosensitive gatekeepers, phase-change materials (PCM) and thermosensitive polymer poly­(N-isopropylacrylamide-co-diethylaminoethyl methacrylate) (PND), to realize precisely the synergy of photothermal and antimicrobial drugs. GNC exhibits an excellent photothermal effect owing to its strong absorbance in the near-infrared (NIR) region, and hollow interiors make it a favorable vehicle for loading various antibiotics such as tetracycline (TC). The release of the encapsulated drugs could be precisely controlled by NIR light through the dual thermosensitive interaction of liquid–solid transition of PCM and coil–granule transition of PND, improving efficacy and alleviating side effects with on-demand drug release. The thermosensitive hydrogel was formed in situ upon application with body temperature, enhancing retention of the antimicrobial agent in local infectious sites. Highly effective ablation of bacteria is achieved both in vitro and in periodontitis models with little toxicity owing to the synergy of photothermal effects and chemotherapeutic drug release induced by NIR. This study could provide guidance for the design of antibacterial materials and shed substantial light on synergistic treatment.

Miscarriage is a frequent complication of human pregnancy: ∼50% to 70% of spontaneous conceptions are lost prior to the second trimester. Etiology of miscarriage includes genetic abnormalities, infections, immunological and implantation disorders, uterine and endocrine abnormalities, and lifestyle factors. Given such variability, knowledge regarding causes, pathophysiological mechanisms, and morphologies of primary early pregnancy loss has significant gaps; often, pregnancy losses remain unexplained. Pathologic evaluation of miscarriage tissue is an untapped source of knowledge. Although miscarriage specimens comprise a significant part of pathologists' workload, information reported from these specimens is typically of minimal clinical utility for delineating etiology or predicting recurrence risk. Standardized terminology is available, though not universally used. We reintroduce the terminology and review new information about early pregnancy losses and their morphologies. Current clinical terminology is inconsistent, hampering research progress. This review is a resource for diagnostic pathologists studying this complex problem.

No abstract