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* Context.--Human epidermal growth factor receptor 2 (HER2) status in breast cancer is currently classified as negative or positive for selecting patients for anti-HER2 targeted therapy. The evolution of the HER2 status has included a new HER2-low category defined as an HER2 immunohistochemistry score of 1+ or 2+ without gene amplification. This new category opens the door to a targetable HER2-low breast cancer population for which new treatments may be effective. Objective.--To review the current literature on the emerging category of breast cancers with low HER2 protein expression, including the clinical, histopathologic, and molecular features, and outline the clinical trials and best practice recommendations for identifying HER2-lowexpressing breast cancers by immunohistochemistry. Data Sources.--We conducted a literature review based on peer-reviewed original articles, review articles, regulatory communications, ongoing and past clinical trials identified through ClinicalTrials.gov, and the authors' practice experience. Conclusions.--The availability of new targeted therapy potentially effective for patients with breast cancers with low HER2 protein expression requires multidisciplinary recognition. In particular, pathologists need to recognize and identify this category to allow the optimal selection of patients for targeted therapy. (Arch Pathol Lab Med. 2024;148:242-255; doi: 10.5858/arpa.2022-0335-RA), Human epidermal growth factor receptor 2 (HER2) is a well-recognized prognostic and predictive biomarker in breast cancer (BC). (1) Clinical assessment of HER2 status is standard of care in patients [...]

Nearly all breast cancer deaths result from metastatic disease. Despite this, the genomic events that drive metastatic recurrence are poorly understood. We performed whole-exome and shallow whole-genome sequencing to identify genes and pathways preferentially mutated or copy-number altered in metastases compared with the paired primary tumors from which they arose. Seven genes were preferentially mutated in metastases--MYLK, PEAK1, SLC2A4RG, EVC2, XIRP2, PALB2, and ESR1--5 of which are not significantly mutated in any type of human primary cancer. Four regions were preferentially copy-number altered: loss of STK11 and CDKN2A/B, as well as gain of PTK6 and the membrane-bound progesterone receptor, PAOR8. PAOR8 gain was mutually exclusive with mutations in the nuclear estrogen and progesterone receptors, suggesting a role in treatment resistance. Several pathways were preferentially mutated or altered in metastases, including mTOR, CDK/ RB, cAMP/PKA, WNT, HKMT, and focal adhesion. Immunohistochemical analyses revealed that metastases preferentially inactivate pRB, upregulate the mTORC1 and WNT signaling pathways, and exhibit nuclear localization of activated PKA. Our findings identify multiple therapeutic targets in metastatic recurrence that are not significantly mutated in primary cancers, implicate membrane progesterone signaling and nuclear PKA in metastatic recurrence, and provide genomic bases for the efficacy of mTORC1, CDK4/6, and PARP inhibitors in metastatic breast cancer., Introduction Breast cancer is the most prevalent cancer in the United States and the leading cause of cancer mortality worldwide among women (1). Although 5-year survival rates approach 90%, up [...]

Immune checkpoint inhibitors (1) result in impressive clinical responses (2-5), but optimal results will require combination with each other (6) and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells ([T.sub.reg] cells), thereby increasing the CD8 T-cell to [T.sub.reg] (CD8/[T.sub.reg]) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/[T.sub.reg] ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms., Anecdotal clinical reports suggest that radiation may cooperate with anti-CTLA4 to systemically enhance melanoma response (7); however, this combination has not been reported in a clinical trial. To examine the [...]

Infiltrating inflammatory cells are highly prevalent within the tumor microenvironment and mediate many processes associated with tumor progression; however, the contribution of specific populations remains unclear. For example, the nature and function of tumor-associated neutrophils (TANs) in the cancer microenvironment is largely unknown. The goal of this study was to provide a phenotypic and functional characterization of TANs in surgically resected lung cancer patients. We found that TANs constituted 5%-25% of cells isolated from the digested human lung tumors. Compared with blood neutrophils, TANs displayed an activated phenotype ([CD62L.sup.lo][CD54.sup.hi]) with a distinct repertoire of chemokine receptors that included CCR5, CCR7, CXCR3, and CXCR4. TANs produced substantial quantities of the proinflammatory factors MCP-1, IL-8, MIP-1α, and IL-6, as well as the antiinflammatory IL-1R antagonist. Functionally, both TANs and neutrophils isolated from distant nonmalignant lung tissue were able to stimulate T cell proliferation and IFN-γ release. Cross-talk between TANs and activated T cells led to substantial upregulation of CD54, CD86, OX40L, and 4-1BBL costimulatory molecules on the neutrophil surface, which bolstered T cell proliferation in a positive-feedback loop. Together our results demonstrate that in the earliest stages of lung cancer, TANs are not immunosuppressive, but rather stimulate T cell responses., Introduction Murine and human studies suggest that tumor initiation and progression are commonly accompanied by 'smoldering' inflammation (1). Tumor-infiltrating myeloid cells represent a significant proportion of the inflammatory cell population [...]

We describe a new mechanism regulating the tumor endothelial barrier and T cell infiltration into tumors. We detected selective expression of the death mediator Fas ligand (FasL, also called CD95L) in the vasculature of human and mouse solid tumors but not in normal vasculature. In these tumors, FasL expression was associated with scarce [CD8.sup.+] infiltration and a predominance of [FoxP3.sup.+] T regulatory ([T.sub.reg]) cells. Tumor-derived vascular endothelial growth factor A (VEGF-A), interleukin 10 (IL-10) and prostaglandin [E.sub.2] ([PGE.sub.2]) cooperatively induced FasL expression in endothelial cells, which acquired the ability to kill effector [CD8.sup.+] T cells but not [T.sub.reg] cells because of higher levels of c-FLIP expression in [T.sub.reg] cells. In mice, genetic or pharmacologic suppression of FasL produced a substantial increase in the influx of tumor-rejecting [CD8.sup.+] over [FoxP3.sup.+] T cells. Pharmacologic inhibition of VEGF and [PGE.sub.2] produced a marked increase in the influx of tumor-rejecting [CD8.sup.+] over [FoxP3.sup.+] T cells that was dependent on attenuation of FasL expression and led to CD8-dependent tumor growth suppression. Thus, tumor paracrine mechanisms establish a tumor endothelial death barrier, which has a critical role in establishing immune tolerance and determining the fate of tumors., Engaging the immune system promises to be a key component of optimal cancer therapy (1). Despite effective strategies to elicit an immune response, effective tumor control depends in part on [...]

Abstract: How can we develop a biblical framework for understanding transformational education? The New Testament provides some keys for doing so. In this article, we look at the verb metamorpho [...]

Breast cancer 1, early onset (BRCA1) expression is often reduced in sporadic breast tumors, even in the absence of BRCA1 genetic modifications, but the molecular basis for this is unknown. In this study, we identified homeobox A9 (HOXA9) as a gene frequently downregulated in human breast cancers and tumor cell lines and noted that reduced HOXA9 transcript levels associated with tumor aggression, metastasis, and patient mortality. Experiments revealed that loss of HOXA9 promoted mammary epithelial cell growth and survival and perturbed tissue morphogenesis. Restoring HOXA9 expression repressed growth and survival and inhibited the malignant phenotype of breast cancer cells in culture and in a xenograft mouse model. Molecular studies showed that HOXA9 restricted breast tumor behavior by directly modulating the expression of BRCA1. Indeed, ectopic expression of wild-type BRCA1 phenocopied the tumor suppressor function of HOXA9, and reducing BRCA1 levels or function inhibited the antitumor activity of HOXA9. Consistently, HOXA9 expression correlated with BRCA1 in clinical specimens and with tumor aggression in patients lacking estrogen receptor/progesterone receptor expression in their breast tissue. These findings indicate that HOXA9 restricts breast tumor aggression by modulating expression of the tumor suppressor gene BRCA1, which we believe provides an explanation for the loss of BRCA1 expression in sporadic breast tumors in the absence of BRCA1 genetic modifications., Introduction Developmental regulators that specify tissue morphogenesis are often functionally subverted in adult tissues to promote cancer (1, 2). In particular, the homeobox (HOX) gene family of morphogenic regulators is [...]

Prostatic adenocarcinoma is the most commonly occurring cancer among men in the United States, second only to skin cancer. Currently, the only definitive method to ascertain the presence of prostatic cancer is by trans-rectal ultrasound (TRUS) directed biopsy. Owing to the poor image quality of ultrasound, the accuracy of TRUS is only 20%-25%. High-resolution magnetic resonance imaging (MRI) has been shown to have a higher accuracy of prostate cancer detection compared to ultrasound. Consequently, several researchers have been exploring the use of high resolution MRI in performing prostate biopsies. Visual detection of prostate cancer, however, continues to be difficult owing to its apparent lack of shape, and the fact that several malignant and benign structures have overlapping intensity and texture characteristics. In this paper, we present a fully automated computer-aided detection (CAD) system for detecting prostatic adenocarcinoma from 4 Tesla ex vivo magnetic resonance (MR) imagery of the prostate. Alter the acquired MR images have been corrected for background inhomogeneity and nonstandardness, novel three-dimensional (3-D) texture features are extracted from the 3-D MRI scene. A Bayesian classifier then assigns each image voxel a 'likelihood' of malignancy for each feature independently. The 'likelihood' images generated in this fashion are then combined using an optimally weighted feature combination scheme. Quantitative evaluation was performed by comparing the CAD results with the manually ascertained ground truth for the tumor on the MRI. The tumor labels on the MR slices were determined manually by an expert by visually registering the MR slices with the corresponding regions on the histology slices. We evaluated our CAD system on a total of 33 two-dimensional (2-D) MR slices from five different 3-D MR prostate studies. Five slices from two different glands were used for training. Our feature combination scheme was found to outperform the individual texture features, and also other popularly used feature combination methods, including AdaBoost, ensemble averaging, and majority voting. Further, in several instances our CAD system performed better than the experts in terms of accuracy, the expert segmentations being determined solely from visual inspection of the MRI data. In addition, the intrasystem variability (changes in CAD accuracy with changes in values of system parameters) was significantly lower than the corresponding intraobserver and interobserver variability. CAD performance was found to be very similar for different training sets. Future work will focus on extending the methodology to guide high-resolution MRI-assisted in vivo prostate biopsies. Index Terms--AdaBoost, CAD, general ensemble method, image analysis, image processing, machine learning, MRI, prostate, segmentation, 3-D texture, 4 tesla.

A parametric method and a nonparametric method for the identification of traveling flexural vibrations are presented and these methods are complemented by a tuning stage capable of generating traveling waves for a wide range of excitation frequencies. It is observed that the low efficiency, in terms of mechanical response level to electrical input power, is a consequent of inexistence of resonance when pure traveling waves are tuned.

Byline: Anjali K. Gupta (1), Daniel E. Soto (1), Michael D. Feldman (2), Jeffrey D. Goldsmith (2), Rosemarie Mick (3), Stephen M. Hahn (1), Mitchell Machtay (1), Ruth J. Muschel (2), W. Gillies McKenna (1) Keywords: EGFR; Akt; Her2; Radiation resistance; LY294002; PI3K Abstract: The 5-year survival rate for patients with stage III non-small cell lung cancer (NSCLC) is 10%. A number of genetic alterations are associated with this disease including mutations and amplifications of EGFR (70%) and Ras (20--30%), both of which are upstream of PI3K. Our previous data show that these regulate tumor radiation sensitivity. Here we ask whether the activation of this pathway has prognostic relevance in NSCLC. Two series of patients were retrospectively analyzed. The first series consisted of 23 Stage III NSCLC patients treated preoperatively with a chemo/radiation protocol. The second consisted of 12 Stage III NSCLC patients treated with chemo/radiation without surgery who had survived more than 2 years. Expression levels of EGFR and Her-2 were assessed by immunohistochemical staining. PI3K signaling was evaluated by staining for phosphorylated Akt (P-Akt), a downstream target of PI3K. The staining for EGFR, Her-2, and P-Akt were related to outcome in the two groups. Additionally, the importance of PI3K signaling was evaluated in 3 NSCLC cell lines using a pharmacological blockade of PI3K by LY294002. In the first series of patients, 43% were positive for EGFR, 5% for Her-2, and 82.6% for P-Akt. Of the survivors, 25% were positive for EGFR, 0% for Her-2, and 42% for P-Akt. For P-Akt, this difference had a probability calculation of 0.003. The three NSCLC cell lines that we tested were found to have high levels of P-Akt. Pharmacologically inhibiting PI3K led to decreased Akt phosphorylation and radio sensitization of all three cell lines. The finding that NSCLC survivors treated by radiation have lower levels of PI3K and Akt signaling is consistent with the idea that inhibition of Akt leads to radio sensitization. This further suggests that Akt might be a useful target for sensitization of NSCLC to radiation. Author Affiliation: (1) Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, 19104, USA (2) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA (3) Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, 19104, USA Article History: Registration Date: 01/01/2004 Accepted Date: 29/03/2004

Ex vivo culture of hematopoietic stem cells is limited by the inability of cytokines to maintain primitive cells without inducing proliferation, differentiation, and subsequent loss of repopulating capacity. We identified recently in extracts of kidney bean and hyacinth bean a mannose-binding lectin, called FRIL, and provide here evidence that this protein appears to satisfy properties of a stem cell preservation factor. FRIL was first identified based on its ability to stimulate NIH 3T3 cells transfected with Flt3, a tyrosine kinase receptor central to regulation of stem cells. Molecular characterization from polypeptide sequencing and identification of the eDNA of hyacinth bean FRIL shows 78% amino acid identity with a mannose-binding lectin of hyacinth beans. Treatment of primitive hematopoietic progenitors in suspension culture with purified hyacinth FRIL alone is able to preserve cells for 1 month without medium changes. In vitro progenitor assays for human hematopoietic cells cultured 3 weeks in FRIL displayed small blast-like colonies that were capable of serial replating and persisted even in the presence of cytokines known to induce differentiation. These results suggest that FRIL is capable of preserving primitive progenitors in suspension culture for prolonged periods. FRIL's clinical utility involving procedures for stem cell transplantation, tumor cell purging before autologous transplantation, and ex vivo cultures used for expansion and stem cell gene therapy currently are being explored.

Context.--We define the scope and needs within the new discipline of computational pathology, a discipline critical to the future of both the practice of pathology and, more broadly, medical practice in general. Objective.--To define the scope and needs of computational pathology. Data Sources.--A meeting was convened in Boston, Massachusetts, in July 2014 prior to the annual Association of Pathology Chairs meeting, and it was attended by a variety of pathologists, including individuals highly invested in pathology informatics as well as chairs of pathology departments. Conclusions.--The meeting made recommendations to promote computational pathology, including clearly defining the field and articulating its value propositions; asserting that the value propositions for health care systems must include means to incorporate robust computational approaches to implement data-driven methods that aid in guiding individual and population health care; leveraging computational pathology as a center for data interpretation in modern health care systems; stating that realizing the value proposition will require working with institutional administrations, other departments, and pathology colleagues; declaring that a robust pipeline should be fostered that trains and develops future computational pathologists, for those with both pathology and nonpathology backgrounds; and deciding that computational pathology should serve as a hub for data-related research in health care systems. The dissemination of these recommendations to pathology and bioinformatics departments should help facilitate the development of computational pathology. (Arch Pathol Lab Med. 2016; 140:41-50; doi: 10.5858/arpa.2015-0093-SA), The recent growth of electronic health records ([EHRs]; including the massive amounts of information in clinical laboratory information systems), coupled with powerful new computational approaches for analyzing large data sets, [...]

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) cloned from the Malayan camp parasite strain is an antigenically distinct malarial protein present on the surface of parasitized erythrocytes (PE). PE can bind to endothelial surfaces of blood vessels, which is responsible for some of the symptoms of malaria. PfEMP1 confers antigenic variation and is the receptor that binds to endothelium. PfEMP1 could be used in a malaria vaccine.

Guided-wave and free-space optical interconnects are compared based on insertio loss, link efficiency, connection density, time delay, and power dissipation fo three types of connection networks. Three types of free-space interconnect systems are analyzed that are representative of a wide variety of free-space systems: space-variant basis-set and space-invarient systems. Results indicate that the connection density of a space-variant free space system has a connection density roughly equivalent to a two level guided-wave system with a pitch of [approximately] 10 [[micro]meter] (for a 1-[[micro]meter] wavelength) and a core refractive index of 2.0. It is also shown that the connection densit of basis-set and space-invariant free-space systems can be several orders of magnitude higher than fundamental limits on the connection density of dual-leve guided-wave interconnect systems when large-scale highly connected networks are employed.

A new method for implementing electrically addressed dynamic optical interconnects is presented. In this approach a phase spatial light modulator (SLM) is combined with a computer-generated hologram (CGH). The phase SLM is used to change the phase of the wave front that illuminates the CGH. Binary orthogonal phase codes are used to address the SLM. The CGH is designed with iterative discrete on-axis encoding so that different wave fronts direct light to different locations. High efficiency can be achieved because of the large number and the small dimensions of pixels in the CGH. The dynamic aspects result from the use of an SLM that may have a relatively small number of relatively large pixels. In this manner a high-efficiency programmable interconnect system with fast reconfiguration time based on current technology devices may be implemented. The CGH-SLM method yields connection efficiencies significantly higher than previous methods that are based on the use of thin optical elements. Simulation results indicate that for switch sizes in the range from 1 X 2 to 1 X 8, connection efficiencies of higher than 1/[square root of] N (where N is the number of possible destinations) are feasible.

Lewis lung carcinoma (3LL)-specific peptides, which exhibit homology to the connexin 37 protein, is isolated and sequenced by repeated fractionation and total acid extraction. The methods use synthetic octamers for the binding of these sequences to H-2K(super b) molecules on RMA-S cells. The process stimulates anti-tumor cytotoxic T lymphocytes.

A double pass holographic connection system, which is a prototype multichip model, lowers the switching energy and optical link latency for optically interconnected processor arrays. Silicon CMOS and GaAs laser array chips are attached to one side of the MCM substrate while etched computer generated holograms are present on the other side. These optical interconnects reduce the dissipated power.

A hybrid-algorithm has been developed that uses the concept of a rapid recursive mean-squared-error (RMSE) function combined with the annealed, multiphase, on-axis capabilities of iterative discrete on-axis (IDO) encoding. High diffraction efficiency and computational speed are obtained through the use of the RMSE algorithm with a constant weighting coefficient in the error function and an iterati initial process for determining phase codes in the output plane. Results for large even spot arrays are presented, and comparisons are made for diffraction efficiency, spot uniformity, and computation spe between the original IDO and the Rmse-based IDO encoding.

Just 3 years ago, I do not think we would have entertained putting a conference like this together. We are literally on the exciting part of a development curve based [...]