Altered p16INK4 and RB1 Expressions Are Associated with Poor Prognosis in Patients with Nonsmall Cell Lung Cancer

p16INK4 and RB1 are two potent cell cycle regulators to control the G1/S transition by interacting with CDK4/6, E2F, and D-type cyclins, respectively. Depending on the tumour type, genetic alterations resulting in the functional inactivation have frequently been reported in both genes. By contrast, much less is known regarding the overexpression of these proteins in the tumor cells. In this study, expressions of p16INK4 RB1, and CDKN2A copy number variances (CNV) in the tumor cells were assessed by immunohistochemistry and fluorescence in situ hybridization (FISH), respectively, in 73 nonsmall cell lung cancer (NSCLC) with known 5-year survivals. The histologic type (P = 0.01), p16INK4 (P = 0.004), and RB1 (P < 0.001) were predictive of survivals. The CDKN2A CNV (P < 0.05) was also significant when compared to those cases without CNV. Therefore, among the molecular genetic prognostic factors, expressions of RB1 and p16INK4 in the tumor cells were the most strongly predictive of adverse outcomes in stage I and II nonsquamous NSCLC

Histological spectrum of pulmonary manifestations in kidney transplant recipients on sirolimus inclusive immunosuppressive regimens

<p>Abstract</p> <p>Background</p> <p>After the introduction of novel effective immunosuppressive therapies, kidney transplantation became the treatment of choice for end stage renal disease. While these new therapies lead to better graft survival, they can also cause a variety of complications. Only small series or case reports describe pulmonary pathology in renal allograft recipients on mTOR inhibitor inclusive therapies. The goal of this study was to provide a systematic review of thoracic biopsies in kidney transplant recipients for possible association between a type of immunosuppressive regimen and pulmonary complications.</p> <p>Methods</p> <p>A laboratory database search revealed 28 of 2140 renal allograft recipients (18 males and 10 females, 25 to 77 years old, mean age 53 years) who required a biopsy for respiratory symptoms. The histological features were correlated with clinical findings including immunosuppressive medications.</p> <p>Results</p> <p>The incidence of neoplasia on lung biopsy was 0.4% (9 cases), which included 3 squamous cell carcinomas, 2 adenocarcinomas, 1 diffuse large B-cell lymphoma, 1 lymphomatoid granulomatosis, and 2 post transplant B-cell lymphoproliferative disorders. Diffuse parenchymal lung disease was identified in 0.4% (9 cases), and included 5 cases of pulmonary hemorrhage, 3 cases of organizing pneumonia and 1 case of pulmonary alveolar proteinosis. Five (0.2%) cases showed histological features indicative of a localized infectious process. Patients on sirolimus had neoplasia less frequently than patients on other immunosuppressive combinations (12.5% vs. 58.3%, <it>p </it>= 0.03). Lung biopsies in 4 of 5 patients with clinically suspected sirolimus toxicity revealed pulmonary hemorrhage as the sole histological finding or in combination with other patterns.</p> <p>Conclusions</p> <p>Our study documents a spectrum of neoplastic and non-neoplastic lesions in renal allograft recipients on current immunosuppressive therapies. Sirolimus inclusive regimens are associated with increased risk of pulmonary toxicity but may be beneficial in cases of posttransplant neoplasia.</p> <p>Virtual Slides</p> <p>The virtual slide(s) for this article can be found here: <url>http://www.diagnosticpathology.diagnomx.eu/vs/3320012126569395</url>.</p

Notch3-dependent β-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC

EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of β-catenin in EGFR TKI resistance has been previously reported, however, the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call “adaptive persisters”. We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here we describe the physical association of Notch3 with β-catenin, leading to increased stability and activation of β-catenin. We demonstrate that the combination of EGFR-TKI and a β-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and β-catenin inhibition in patients with EGFR mutant lung cancer

Crosstalk between Chemokine Receptor CXCR4 and Cannabinoid Receptor CB2 in Modulating Breast Cancer Growth and Invasion

Cannabinoids bind to cannabinoid receptors CB(1) and CB(2) and have been reported to possess anti-tumorigenic activity in various cancers. However, the mechanisms through which cannabinoids modulate tumor growth are not well known. In this study, we report that a synthetic non-psychoactive cannabinoid that specifically binds to cannabinoid receptor CB(2) may modulate breast tumor growth and metastasis by inhibiting signaling of the chemokine receptor CXCR4 and its ligand CXCL12. This signaling pathway has been shown to play an important role in regulating breast cancer progression and metastasis.We observed high expression of both CB(2) and CXCR4 receptors in breast cancer patient tissues by immunohistochemical analysis. We further found that CB(2)-specific agonist JWH-015 inhibits the CXCL12-induced chemotaxis and wound healing of MCF7 overexpressing CXCR4 (MCF7/CXCR4), highly metastatic clone of MDA-MB-231 (SCP2) and NT 2.5 cells (derived from MMTV-neu) by using chemotactic and wound healing assays. Elucidation of the molecular mechanisms using various biochemical techniques and confocal microscopy revealed that JWH-015 treatment inhibited CXCL12-induced P44/P42 ERK activation, cytoskeletal focal adhesion and stress fiber formation, which play a critical role in breast cancer invasion and metastasis. In addition, we have shown that JWH-015 significantly inhibits orthotopic tumor growth in syngenic mice in vivo using NT 2.5 cells. Furthermore, our studies have revealed that JWH-015 significantly inhibits phosphorylation of CXCR4 and its downstream signaling in vivo in orthotopic and spontaneous breast cancer MMTV-PyMT mouse model systems.This study provides novel insights into the crosstalk between CB(2) and CXCR4/CXCL12-signaling pathways in the modulation of breast tumor growth and metastasis. Furthermore, these studies indicate that CB(2) receptors could be used for developing innovative therapeutic strategies against breast cancer

Papillary fibroelastoma arising from the coumadin ridge

Cardiac papillary fibroelastomas (CPF) are rare cardiac tumors, mostly found on the valvular surfaces in the heart. These tumors are frond like in nature and are benign, intracardiac masses, rarely causing any hemodynamic disturbances. However, excision of these masses is indicated due to their propensity to embolize. We present a case report of the tumor found on the coumadin ridge, causing transient ischemic attacks in a patient. We performed complete excision of the tumor via median sternotomy on cardiopulmonary bypass support with cardiac arrest. The diagnosis was confirmed by histological examination. The patient had an uneventful postoperative course and was discharghed on postoperative day 4. She has had complete resolution of her symptoms post excision. The diagnosis of the mass was confirmed on histological examination

Pulmonary hematoidin deposition in a case of severe COVID19 pneumonia

A 59-year-old male with past medical history significant for hypertension, coronary artery disease, atrial fibrillation, hyperlipidemia, obesity, obstructive sleep apnea and deep vein thrombosis developed severe COVID19 pneumonia. His clinical course was noted for progressive respiratory failure that subsequently resulted in bilateral lung transplantation. Examination of the explanted lungs was notable for the presence of extensive grossly apparent bright yellow discolorations that histologically represented hematoidin deposits. The background lung was affected by diffuse alveolar damage, accompanied by infarcts and organizing thrombi. This case suggests that a combination of acute lung injury and thrombotic complications in severe COVID19 pneumonia can facilitate formation of pockets of anoxic environment leading to hematoidin deposition within lung tissue

Impact of tillage and crop rotations on soil organic matter content in Northern Kazakhstan's chernozem soils: A 10-year study (2011-2021)

This extensive 10-year study conducted in Northern Kazakhstan investigates the intricate relationship between soil management techniques, crop rotations, and soil organic matter (SOM) content in Chernozem soils, an essential agricultural resource in the region. The experiments were established at the Karabalyk Agricultural Experimental Station, characterized by a arid continental climate. The study systematically examined the impact of two primary soil management techniques, conventional tillage (CT) and no-tillage (NT), in combination with various crop rotations. The crop rotations tested included grain-fallow rotations, fruit-exchange crop rotations, and an eight-field fruit-exchange crop rotation. The results provide valuable insights into the sustainable management of Chernozem soils in arid conditions, underscoring the role of crop rotation strategies in preserving SOM content. The findings reveal that among the crop rotations tested, the eight-field fruit-exchange crop rotation exhibited the most favorable outcomes for SOM preservation. This rotation helped maintain relatively stable SOM levels over the 10-year study period, contributing to soil health and fertility. In the context of the region's arid climate, the choice of soil management technique (CT or NT) had a limited impact on SOM content. The stability of SOM levels across diverse crop rotations and years highlights the dominant influence of crop management practices in this distinctive agricultural environment. This research serves as a valuable reference for tailored approaches to ensure soil health and organic matter preservation in the unique conditions of Northern Kazakhstan. It promotes the adoption of diversified crop rotations, with particular emphasis on the effectiveness of the eight-field fruit-exchange crop rotation, as a powerful strategy to mitigate organic matter loss, enhance soil quality, and optimize soil fertility in arid agricultural landscapes. The insights gained from this study are vital for sustainable land management in the region and underscore the importance of region-specific, holistic investigations to guide effective agricultural practices. The findings offer a solid foundation for the development of strategies that address soil health and safeguard the integrity of essential soil resources in these unique environments. The study conducted at the Karabalyk Agricultural Experimental Station in Northern Kazakhstan between 2011 and 2021 provides critical insights into the relationship between soil management techniques, crop rotations, and SOM content in Chernozem soils. The research suggests that diversified crop rotations, particularly the eight-field fruit-exchange crop rotation, represent a promising approach for mitigating organic matter loss and enhancing soil quality in arid regions

Metastatic Squamous Cell Carcinoma Component from an Adenosquamous Carcinoma of the Lung with Identical Epidermal Growth Factor Receptor Mutations

The case reported is a young “light” ex-smoker who initially had a localized adenosquamous carcinoma bearing an epidermal growth factor receptor (EGFR) sensitizing mutation. He first recurred six months after initial treatment within the brain with a pure squamous histology and the same EGFR mutation. Surgical resection and radiation rendered him disease-free. Subsequent isolated recurrence within the lung eighteen months later was a pure adenocarcinoma, again with the same identified EGFR mutation. These histologic changes (from adenosquamous to pure squamous to pure adenocarcinoma) have been described but not before in the absence of any selection pressure with EGFR tyrosine kinase inhibitors. This case points out the histologic “flexibility” of EGFR mutant lung cancers and the importance for appropriate molecular testing in nonsmokers with lung cancer of any histologic type