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Trever Bivona and colleagues use an in vivo lung cancer metastasis model to show that the transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. CIC inactivation leads to upregulation of ETV4 and MMP24, which is necessary and sufficient for metastasis. Metastasis is the leading cause of death in people with lung cancer, yet the molecular effectors underlying tumor dissemination remain poorly defined. Through the development of an in vivo spontaneous lung cancer metastasis model, we show that the developmentally regulated transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. Inactivation of CIC relieves repression of its effector ETV4 , driving ETV4-mediated upregulation of MMP24, which is necessary and sufficient for metastasis. Loss of CIC, or an increase in levels of its effectors ETV4 and MMP24, is a biomarker of tumor progression and worse outcomes in people with lung and/or gastric cancer. Our findings reveal CIC as a conserved metastasis suppressor, highlighting new anti-metastatic strategies that could potentially improve patient outcomes.

In March 2009, a novel swine-origin influenza A/H1N1 virus was identified. After global spread, the World Health Organization in June declared the first influenza pandemic in 41 years. To describe the clinicopathologic characteristics of 34 people who died following confirmed A/H1N1 infection with emphasis on the pulmonary pathology findings. We reviewed medical records, autopsy reports, microbiologic studies, and microscopic slides of 34 people who died between May 15 and July 9, 2009, and were investigated either by the New York City Office of Chief Medical Examiner (32 deaths) or through the consultation service of a coauthor (2 deaths). Most of the 34 decedents (62%) were between 25 and 49 years old (median, 41.5 years). Tracheitis, bronchiolitis, and diffuse alveolar damage were noted in most cases. Influenza viral antigen was observed most commonly in the epithelium of the tracheobronchial tree but also in alveolar epithelial cells and macrophages. Most cases were reverse transcription-polymerase chain reaction positive for influenza. Histologic and microbiologic autopsy evidence of bacterial pneumonia was detected in 55% of cases. Underlying medical conditions including cardiorespiratory diseases and immunosuppression were present in 91% of cases. Obesity (body mass index, >30) was noted in 72% of adult and adolescent cases. The pulmonary pathologic findings in fatal disease caused by the novel pandemic influenza virus are similar to findings identified in past pandemics. Superimposed bacterial infections of the respiratory tract were common. Preexisting obesity, cardiorespiratory diseases, and other comorbidities also were prominent findings among the decedents.

After sequential treatment with first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), EGFR-mutant non-small cell lung cancers frequently harbor multiple resistance mutations in exon 20 of EGFR including T790M, mediating resistance to first-generation TKIs, and at codons 792, 796, or 797 mediating resistance to third-generation TKIs. However, whether these resistance mutations are in cis or trans has therapeutic implications for patients. We analyzed a cohort of 29 patients with NSCLC harboring EGFR mutations at codons 792, 796, or 797 to establish the configuration of these mutations. We performed hybrid capture-based, next-generation sequencing on formalin-fixed paraffin-embedded biopsy tissue or liquid biopsy. 27 samples had both a T790M mutation and a mutation at codons 792, 796, or 797. In all of these cases, the mutations were found in the cis configuration; the trans configuration was not observed. Two patients' samples harbored a mutation at codon 797 but no T790M mutation. In these two cases, longitudinal analysis showed earlier biopsies harbored EGFR T790M, which was undetectable following osimertinib treatment. Treatment of one these patients with both first- and third-generation EGFR TKIs resulted in a mixed response. Here we describe multiple configurations of EGFR T790M and third-generation TKI resistance mutations at codons 792, 796, and 797. These mutations are most commonly found in cis, which confers resistance to all current EGFR TKIs. We also describe two patients that exhibited T790M loss with acquisition of a mutation at codon 797. In addition, one of these patients, with an EGFR C797S in a lung biopsy was subsequently found to have EGFR C797N in a later biopsy of pleural fluid, highlighting the dynamic multiclonal nature of advanced NSCLC.

Purpose Malignant phyllodes tumors (MPT) are exceptionally rare, and the genomic drivers of these tumors are still being elucidated. We performed comprehensive genomic profiling (CGP) of MPT to identify genomic alterations that will inform approaches to targeted therapy for patients with MPT, including relapsed, refractory, and metastatic disease. Methods DNA was extracted from formalin-fixed, paraffin-embedded samples from 24 consecutive patient cases of MPT. CGP was performed using a hybrid capture, adaptor ligation-based next generation sequencing assay to a high, uniform coverage (mean, 582×). Tumor mutational burden (TMB) was calculated from a minimum of 1.14 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations, including short variants (SV; base substitutions, small insertions, and deletions), rearrangements, and copy number changes, including amplifications and homozygous deletions. Results The 24 cases of MPT included 15 patients with localized and 9 with metastatic disease. The median TMB was 2.7 mut/Mb, and no cases had a TMB > 10 mut/Mb. 20 out of 24 cases were evaluable for microsatellite status, and all were microsatellite stable. The most commonly mutated genes were TP53 (58.3%), TERT -promoter (57.9%), NF1 (45.8%), MED12 (45.8%), CDKN2A/B (33.3%), and MLL2 (33.3%). Targetable kinase fusions including KIAA1549 - BRAF or FGFR3 - TACC3 were identified in 2/24 (8.3%) tumors. Conclusions This study identifies clinically relevant genomic alterations that suggest novel targeted therapy approaches for patients with MPT.

This project explores the Christian life as active participation in the present reality of God’s kingdom, challenging the common notion that faith is primarily about going to heaven after death. Drawing on the biblical framework of inaugurated eschatology, it argues that Jesus’ proclamation of the kingdom was not only future- oriented but also deeply present and powerful in the here and now. This understanding reshapes discipleship, prayer, and the mission of the church, calling believers to live in the transforming power of the kingdom today in every sphere of life. This project calls believers to embrace a kingdom-centered life shaped by Jesus’ teaching, where living with God is not a future hope but a present reality. Drawing from the insights of George Eldon Ladd, N. T. Wright, Mark Saucy, and Dallas Willard, it presents the Lord’s Prayer as a practical invitation to live under God’s reign now, seeking his will, embodying kingdom values, and participating in his redemptive work in the world.

Purpose Pure mucinous breast carcinoma (pmucBC) is a distinctive variant of breast cancer (BC) featuring an excellent overall prognosis. However, on rare occasions, pmucBC pursues an aggressive clinical course. We queried whether comprehensive genomic profiling (CGP) would uncover clinically relevant genomic alterations (CRGA) that could lead to targeted therapy treatment for patients with an advanced and metastatic form of pmucBC. Methods From a series of 51,238 total cancer samples, which included 5605 cases of clinically advanced BC and 22 cases of stage IV pmucBC, DNA was extracted from 40 microns of FFPE sections. Comprehensive genomic profiling was performed using a hybrid-capture, adaptor ligation-based next generation sequencing assay to a mean coverage depth of 564X. The results were analyzed for all classes of genomic alterations (GA) including base substitutions, insertions and deletions, select rearrangements, and copy number changes. Clinically relevant genomic alterations were defined as those indicating possible treatment with anti-cancer drugs on the market or in registered clinical trials. Results Samples were obtained from breast (11), lymph nodes (3), chest wall (2), liver (2), soft tissue (2), bone (1), and pleura (1). The median age of the 22 pmucBC patients was 57 years (range 32–79 years). Three pmucBCs were grade 1, 17 were grade 2, and 2 were grade 3. Twenty-one (95 %) pmucBC were ER+, 18 (82 %) were PR+, and 3 (14 %) were HER2+ by IHC and/or FISH. A total of 132 GA were identified (6.0 GA per tumor), including 53 CRGA, for a mean of 2.4 GA per tumor. Amplification of FGFR1 or ZNF703 , located within the same amplicon, was found in 8 of 22 cases (36 %). This enrichment of FGFR1 amplification in 36 % of pmucBC versus 11 % of non-mucinous ER+ BC (601 cases) was significant ( p  < 0.005). Other frequently altered genes of interest in pmucBC were CCND1 and the FGF3/FGF4/FGF19 amplicon (27 %), often co-amplified together. ERBB2/HER2 alterations were identified in 5 pmucBC (23 %): ERBB2 amplification was found in 3 of 3 cases (100 %) that were HER2+ by IHC and/or FISH; 1 pmucBC was negative for HER2 overexpression by IHC, but positive for amplification by CGP; and 2 pmucBC harbored the ERBB2 substitutions D769Y and V777L (one sample also featured ERBB2 amplification). The enrichment of ERBB2 GA in metastatic pmucBC versus non-metastatic primary pmucBC was significant ( p  = 0.03). CRGA were also found in 20 additional genes including PIK3CA (5), BRCA1 (1), TSC2 (1), STK11 (1), AKT3 (1), and ESR1 (1). Conclusions Metastatic pmucBC is a distinct form of breast cancer that features a relatively high frequency of CRGA, including a significant enrichment of FGFR1 alterations and a high frequency of ERBB2 alterations when compared with non-metastatic pmucBC. These findings suggest that CGP can identify a variety of known and emerging therapy targets that have the potential to improve outcomes for patients with clinically advanced and metastatic forms of this disease.

True mesothelial (epithelial) cysts in the adrenal gland are rare lesions. They represent 9% of adrenal cysts and are much less common than vascular adrenal cysts. We report a case of a true adrenal mesothelial cyst in a patient with flank pain and hematuria that was diagnosed on imaging as a renal cyst. Immunohistochemical studies were performed to investigate the nature of the cyst lining. The positive immunostains for calretinin and WT-1 lend support to the postulate of Medeiros et al nearly 20 years ago of a mesothelial origin for these cysts. The clinical presentation and salient radiologic and pathologic features are described.

Internet advertising has become a growing source of frustration for Internet users. The phrase Internet advertising immediately conjures up thoughts of closing annoying pop-up advertisements and sorting through countless unsolicited e-mail advertisements. These negative connotations often overshadow the increasing value of the Internet as a free, extensive source of information. In fact, the Internet has created a more informed consumer. Advertisers, realizing the importance of reaching Internet consumers, have rushed onboard. As a result, the attention of these educated consumers has become valuable currency on the Internet. Not surprisingly, the anonymity and ease of access of the Internet has spawned abuse by advertisers, including spam and unsolicited pop-up advertisements. However, legitimate Internet advertising supports and maintains the industry. The practices of one of the first pop-up advertising vendors, Gator Corporation, have been the subject of recent litigation. The plaintiffs, owners and operators of Internet websites, have argued that Gator's practice of causing pop-up ads to appear over their websites violates their intellectual property rights. This Note evaluates existing trademark, unfair competition, and copyright standards and applies them to Gator's pop-up advertising scheme. It also evaluates some of the earliest federal cases concerning pop-up advertising and their disparate outcomes.

The stability of the protein human α-Lactalbumin (HLA) after binding of a series of metal cations including Mg2+, Zn2+, Cd2+, Co2+, Mn2+ , Sr2+, Ca2+, Na+ and K+ has been examined and compared with that of α-lactalbumin from other species by monitoring the fluorescence of tryptophan residues upon thermal-induced denaturation. The melting temperature (Tm) was determined from the λmax data as well as the fluorescence intensity data. Mathematical expressions for determining thermodynamic parameters (ΔH, ΔG and ΔS) were introduced based on the assumption that the thermal denaturing process was a simple two-state model between the folded state and the unfolded state. These newly developed expressions are especially useful because they allow one to easily calculate the thermodynamic parameters at every temperature as long as the fitting parameters are known. The thermal-induced unfolding experiments revealed that the binding of metal ions to apo-α-lactalbumin was found to increase the stability, but the degree of stabilization varied significantly for each metal ion. From the λmax data and the fluorescence intensity data, the melting temperatures ranged from 28.15°C to 63.59°C and from 26.12°C to 64.42°C, respectively. At Tm, ΔH and ΔS were determined to range from 129.19 kJ/mol to 273.69 kJ/mol and from 0.40 kJ/mol·K to 0.81 kJ/mol·K, respectively. At physiological temperature (37°C), ΔH and ΔS were determined to range from 121.84 kJ/mol to 238.65 kJ/mol and from 0.38 kJ/mol·K to 0.68 kJ/mol·K, respectively. At Tm, ΔG was 0 as expected, but it ranged from −5.29 kJ/mol to 19.91 kJ/mol at 37°C. Overall, the monovalent cations Na+ and K + were found to destabilize HLA whereas the divalent cations Mg 2+, Zn2+, Cd2+, Co2+, Mn2+, Sr2+ and Ca2+ were found to stabilize HLA. As α-lactalbumin is a Ca2+-binding protein, Ca2+ was found to have the greatest effect on the protein stability with the Tm value of 63.59°C.

To improve the efficiency of photon upconversion, a hybrid approach of combining organic dyes and inorganic nanoparticles is proving successful, especially in the form of dye-sensitized lanthanide-doped upconversion nanoparticles, nanoparticle-sensitized molecular triplet–triplet annihilation systems and metal–organic-framework nanoparticles. In this Review, we survey the latest advances and examine the key factors affecting upconversion performance, such as spectral overlap, core–shell design and the management of triplet excitons and quenchers at the interface between materials. Although issues such as stability, triplet-state quenching, concentration quenching and reabsorption must still be overcome, smart designs of hybrid nanosystems offer exciting opportunities for applications such as solar photovoltaic devices, deep-tissue biomedical imaging, optogenetics and nanomedicine among others.