tbuckley/cabot-search huggingface dataset:
Neoadjuvant Trastuzumab Induces Apoptosis in Primary Breast Cancers
Authors: Syed K. Mohsin, Heidi L. Weiss, M. Carolina Gutierrez, Gary C. Chamness, Rachel Schiff, Michael P. DiGiovanna, Chun-Xia Wang, Susan G. Hilsenbeck, C. Kent Osborne, D. Craig Allred, Richard Elledge, Jenny C. Chang
Journal: Journal of Clinical Oncology (2005)

Purpose Greater understanding of the cellular response in trastuzumab-treated patients will provide insight into the clinical management of patients. Patients and Methods We performed a neoadjuvant trial in 35 patients with locally advanced HER-2/neu overexpressing breast cancers who received weekly trastuzumab given as a single agent for the first 3 weeks, followed by a combination of trastuzumab and docetaxel for 12 weeks before surgery. Sequential core biopsies were taken at baseline and within weeks 1 and 3 after the first dose of trastuzumab. Clinical response to trastuzumab was assessed by tumor measurements on day 22 before chemotherapy. Core biopsies were assessed by immunohistochemistry for cell cycle and proliferation (Ki67, p27, phosphorylated [p] -MAPK), apoptosis and survival (apoptotic index, p-Akt), epidermal growth factor receptor, and total and p-HER-2. Results There was early tumor regression with a median decrease of −20.0% (range. 0% to 60.4%) after only 3 weeks of trastuzumab, and eight patients (23%) had a partial response. Consistent with the clinical regressions, apoptosis was significantly induced (median increase from 3.5% to 4.7%; P = .006) within week 1, a 35% increase above baseline. No significant change in epidermal growth factor receptor score was observed in week 1, without changes in total or p-HER-2 expression. Tumors with high baseline Ki67 were less likely to respond (P = .02). Conclusion In primary breast cancers, trastuzumab substantially induces apoptosis, providing a molecular explanation for both its therapeutic efficacy and its successful combination with cytotoxic chemotherapy.
Differences in Prognostic Molecular Markers between Women Over and Under 45 Years of Age with Advanced Ovarian Cancer
Authors: John K. Chan, Vera Loizzi, Alessandra Magistris, Fritz Lin, Joanne Rutgers, Kathryn Osann, Philip J. DiSaia, Michael L. Berman
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this study was to determine whether differences in molecular markers might explain the better prognosis of women ≤45 years of age versus women &amp;gt;45 years of age diagnosed with ovarian cancers. Experimental Design: Tissue sections from women with stage III–IV ovarian cancers were examined for expression of CD34, p53, and HER2. The Kaplan-Meier method and Cox Proportional Hazard analyses were used to identify predictors for outcome. Results: Fifty-two women ≤45 years of age were matched with 52 women who were &amp;gt;45 years old. Of the 46 available tissue sections, 24 were from the younger age group (mean age, 41 years), and 22 were from the older age group (mean age, 61 years). Based on CD34 expression, tumors from women &amp;gt;45 years of age had lower microvessel density (MVD) compared with tumors of younger women (10.3 versus 16.1 microvessels per ×400 field; P = 0.03). Lower MVD (≤11 microvessels per ×400 field) predicted for a worse prognosis than higher MVD (&amp;gt;11 microvessels per ×400 field) in the overall study group (P = 0.001) and within the older subgroup (P = 0.03). The expressions of p53 (P = 0.13) and HER2 (P = 0.49) did not vary between the two age groups. The median survivals of those with tumors that overexpressed p53 and HER2 were 28.6 and 23.9 months compared with 51.7 and 38.6 months in those with cancers that underexpressed these markers, respectively (P = 0.09 for p53, P = 0.15 for HER2). Conclusions: Ovarian cancers in women &amp;gt;45 years of age had lower MVD compared with those in women ≤45 years of age. Lower MVD was an independent prognostic factor for decreased survival. Lower frequency of neovascularization in these cancers may contribute to the decreased survival observed in women &amp;gt;45 years of age.
The severity of steatosis influences liver stiffness measurement in patients with nonalcoholic fatty liver disease
Authors: Salvatore Petta, Marcello Maida, Fabio Salvatore Macaluso, Vito Di Marco, Calogero Cammà, Daniela Cabibi, Antonio Craxì
Journal: Hepatology (2015)

In nonalcoholic fatty liver disease, the influence of severity of steatosis on liver stiffness measurement (LSM) is poorly studied and still debated. We assessed the impact of steatosis severity and its ultrasonographic (US) sign, severe bright liver echo pattern, on LSM values and on transient elastography accuracy for the diagnosis of liver fibrosis in a cohort of consecutive patients with nonalcoholic fatty liver disease. Patients (n = 253) were assessed by clinical, US, and histological (Kleiner score) features. Transient elastography was performed using the M probe. Among patients with low amounts of fibrosis (F0-F1 and F0-F2), median LSM values, expressed in kilopascals, were significantly higher in subjects with severe steatosis (≥66% at liver biopsy) compared to those without (F0-F1 6.9 versus 5.8, P = 0.04; F0-F2 7.4 versus 6.0, P = 0.001) as well as in patients with severe bright liver echo pattern on US compared to their counterparts (F0-F1 7.3 versus 5.6, P = 0.001; F0-F2 7.6 versus 6.0, P < 0.001). In subjects without significant fibrosis (F0-F1) and without severe fibrosis (F0-F2), a higher rate of false-positive LSM results was observed in patients with steatosis ≥66% compared to those without (F0-F1 23.6% versus 14.9%, F0-F2 33.3% versus 13.2%) and in patients with severe bright liver echo pattern on US (F0-F1 22.2% versus 15.4%, F0-F2 28.8% versus 15.6%) compared to their counterparts.In patients with nonalcoholic fatty liver disease, the presence of severe steatosis, detected by histology or by US, should always be taken into account in order to avoid overestimations of liver fibrosis assessed by transient elastography.
Incidence of brain metastasis at initial presentation of lung cancer
Authors: J. Lee Villano, Eric B. Durbin, Chris Normandeau, Jigisha P. Thakkar, Valentina Moirangthem, Faith G. Davis
Journal: Neuro-Oncology (2014)

No reliable estimates are available on the incidence of brain metastasis (BM) in cancer patients. This information is valuable for planning patient care and developing measures that may prevent or decrease the likelihood of metastatic brain disease.We report the first population-based analysis on BM incidence at cancer diagnosis using the Kentucky Cancer Registry (KCR) and Alberta Cancer Registry (ACR). All cancer cases with BM were identified from KCR and ACR, with subsequent focus on metastases from lung primaries; the annual number of BMs at initial presentation was derived. Comparisons were made between Kentucky and Alberta for the stage and site of organ involvement of lung cancer.Low incidence of BM was observed in the United States until mandatory reporting began in 2010. Both the KCR and ACR recorded the highest incidence of BM from lung cancer, with total BM cases at initial presentation occurring at 88% and 77%, respectively. For lung cancer, stage IV was the most common stage at presentation for both registries and ranged from 45.9% to 57.2%. When BM from lung was identified, the most common synchronous organ site of metastasis was osseous, occurring at 28.4%.Our analysis from the Kentucky and Alberta cancer registries similarly demonstrated the aggressive nature of lung cancer and its propensity for BM at initial presentation. Besides widespread organ involvement, no synchronous organ site predicted BM in lung cancer. BM is a common and important clinical outcome, and use of registry data is becoming more available.
Characterization of the early stages of thymic NKT cell development
Authors: Kamel Benlagha, Datsen G. Wei, Joel Veiga, Luc Teyton, Albert Bendelac
Journal: The Journal of Experimental Medicine (2005)

Upon reaching the mature heat stable antigen (HSA)low thymic developmental stage, CD1d-restricted Vα14-Jα18 thymocytes undergo a well-characterized sequence of expansion and differentiation steps that lead to the peripheral interleukin-4/interferon-γ–producing NKT phenotype. However, their more immature HSAhigh precursors have remained elusive, and it has been difficult to determine unambiguously whether NKT cells originate from a CD4+CD8+ double-positive (DP) stage, and when the CD4+ and CD4−CD8− double-negative (DN) NKT subsets are formed. Here, we have used a CD1d tetramer-based enrichment strategy to physically identify HSAhigh precursors in thymuses of newborn mice, including an elusive DPlow stage and a CD4+ stage, which were present at a frequency of ∼10−6. These HSAhigh DP and CD4+ stages appeared to be nondividing, and already exhibited the same Vβ8 bias that characterizes mature NKT cells. This implied that the massive expansion of NKT cells is separated temporally from positive selection, but faithfully amplifies the selected TCR repertoire. Furthermore, we found that, unlike the DN γδ T cells, the DN NKT cells did not originate from a pTα-independent pathway bypassing the DP stage, but instead were produced during a short window of time from the conversion of a fraction of HSAlow NK1.1neg CD4 cells. These findings identify the HSAhigh CD4+ stage as a potential branchpoint between NKT and conventional T lineages and between the CD4 and DN NKT sublineages.
HER Targeting in HER2-Negative Breast Cancers: Looking for the HER3 Positive
Authors: Marcia R. Campbell, Mark M. Moasser
Journal: Clinical Cancer Research (2015)

Targeting HER2 for the treatment of HER2-positive breast cancers is now a validated treatment paradigm. However, evidence suggests that this family of receptors may have important roles outside of the realm of HER2 amplification. There is considerable interest in the development of biomarkers to identify such breast cancers.
Mechanisms by which saturated triacylglycerols elevate the plasma low density lipoprotein-cholesterol concentration in hamsters. Differential effects of fatty acid chain length.
Authors: L A Woollett, D K Spady, J M Dietschy
Journal: Journal of Clinical Investigation (1989)

These studies were designed to elucidate how shorter (MCT) and longer (HCO) chain-length saturated triacylglycerols and cholesterol interact to alter steady-state plasma LDL-cholesterol levels. When either MCT or HCO was fed in the absence of cholesterol, there was little effect on receptor-dependent LDL transport but a 36-43% increase in LDL-cholesterol production. Cholesterol feeding in the absence of triacylglycerol led to significant suppression of receptor-dependent LDL transport and a 26-31% increase in LDL-cholesterol production. However, when the longer chain-length saturated triacylglycerol was fed together with cholesterol there was a marked increase in the suppression of receptor-dependent LDL transport and an 82% increase in production rate. Together, these two alterations accounted for the observed eightfold increase in plasma LDL-cholesterol concentration. In contrast, feeding the shorter chain-length saturated triacylglycerol with cholesterol actually enhanced receptor-dependent LDL transport while also causing a smaller increase (52%) in the LDL-cholesterol production rate. As a result of these two opposing events, MCT feeding had essentially no net effect on plasma LDL-cholesterol levels beyond that induced by cholesterol feeding alone.
Intravitreal Injection of Triamcinolone
Authors: Michael S. Ip
Journal: Diabetes Care (2004)

Editor’s comment: From time to time, treatments for diabetes and its complications are promulgated, which seem to have sufficient nonrandomized clinical data to support their consideration for use in our patients. Rather than wait for randomized clinical trials to be published (and in some cases, this is unlikely to occur), descriptions of these treatments, their effectiveness, and their side effects will be published in Diabetes Care as a Commentary. In many situations, these therapeutic approaches would only be considered after more conventional therapy has been ineffective. Intraocular injections of glucocorticoids for macular edema fit these criteria. 

Diabetic retinopathy is a major cause of visual impairment in the U.S. (1–3). Diabetic macular edema is a manifestation of diabetic retinopathy that produces loss of central vision and is commonly diagnosed by ophthalmologists. The Wisconsin Epidemiologic Study of Diabetic Retinopathy estimated that after 15 years of known diabetes, the prevalence of diabetic macular edema is ∼20% in patients with type 1 diabetes, 25% in patients with type 2 diabetes who are taking insulin, and 14% in patients with type 2 diabetes who do not take insulin (1).

Diabetic macular edema, because of the frequency with which it is seen, is a condition that has considerable public health importance. Currently, the only demonstrated means to reduce the risk of vision loss from diabetic macular edema are intensive glycemic control, as demonstrated by the Diabetes Control and Complications Trial (DCCT) (4) and the U.K. Prospective Diabetes Study (5), and laser photocoagulation, as demonstrated by the Early Treatment Diabetic Retinopathy Study (ETDRS) (6).

In the DCCT, intensive glucose control reduced the risk of onset of diabetic macular edema by 23% compared with conventional treatment. Long-term follow-up of patients in the DCCT show a sustained effect of intensive glucose control, with a 58% …
Epigenetic repression of ROR2 has a Wnt-mediated, pro-tumourigenic role in colon cancer
Authors: Ester Lara, Vincenzo Calvanese, Covadonga Huidobro, Agustin F Fernández, Ángela Moncada-Pazos, Álvaro J Obaya, Oscar Aguilera, José Manuel González-Sancho, Laura Sánchez, Aurora Astudillo, Alberto Muñoz, Carlos López-Otín, Manel Esteller, Mario F Fraga
Journal: Molecular Cancer (2010)

Abstract Background Wnt factors control cell differentiation through semi-independent molecular cascades known as the β-catenin-dependent (canonical) and -independent (non-canonical) Wnt signalling pathways. Genetic and epigenetic alteration of components of the canonical Wnt signalling pathway is one of the primary mechanisms underlying colon cancer. Despite increasing evidence of the role of the non-canonical pathways in tumourigenesis, however, the underlying molecular mechanisms are poorly understood. Results Here we report that the receptor tyrosine kinase-like orphan receptor 2 (ROR2), a transmembrane receptor for Wnt factors that activates non-canonical pathways, is frequently repressed by aberrant promoter hypermethylation in human colon cancer cell lines and primary tumours. By restoring ROR2 activity in colon cancer cells harbouring ROR2 promoter hypermethylation, we show that the role of ROR2 in colon cancer cells is mediated, at least in part, by canonical Wnt and that its epigenetic-dependent loss can be pro-tumourigenic. Conclusions Our data show the importance of epigenetic alterations of ROR2 in colon cancer, highlighting the close interconnection between canonical and non-canonical Wnt signalling pathways in this type of tumour.
Successful Management of Cobra Bite with Cryotherapy
Authors: J. Fred Mullins
Journal: JAMA (1960)

Cryotherapy was used in a case of envenomization by a cobra (Naja naja). The patient, a 17-year-old male snake handler, was bitten on the left index finger. Systemic administration of steroids was also begun at once, but specific antivenin was not obtainable for nine hours. Although death sometimes occurs 8 to 12 hours after cobra envenomization, and in spite of the lack of specific cobra antivenin for 9 hours, no symptoms of systemic intoxication developed. Morbidity was confined to the envenomized arm, which became markedly swollen when cryotherapy was discontinued after 37 hours. Severe local destruction at the site of the bite eventually necessitated amputation of the distal portion of the involved finger.
C-Kit–Positive Cells Accumulate in Remodeled Vessels of Idiopathic Pulmonary Arterial Hypertension
Authors: David Montani, Frédéric Perros, Natalia Gambaryan, Barbara Girerd, Peter Dorfmuller, Laura C. Price, Alice Huertas, Hamida Hammad, Bart Lambrecht, Gérald Simonneau, Jean-Marie Launay, Sylvia Cohen-Kaminsky, Marc Humbert
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

C-kit(+) cells, including bone marrow (BM)-derived progenitors and mast cells, may participate in vascular remodelling. Because recent studies suggest that c-kit may be a target for innovative therapies in experimental pulmonary hypertension, we investigated the contribution of c-kit(+) cells in human idiopathic pulmonary arterial hypertension (IPAH).To investigate the contribution of c-kit(+) cells in human IPAH.Single c-kit, CXCL12/SDF-1α, CXCR4, CD34, and multiple c-kit, α-smooth muscle actin (α-SMA) and tryptase immunostainings were performed in IPAH lungs. C-kit mRNA expression was quantified by real-time polymerase chain reaction in microdissected pulmonary arteries from patients with IPAH and control subjects. Phenotype and function of circulating progenitors were analyzed by flow cytometry. Plasma levels of soluble c-kit and CXCL12/SDF-1α were measured by ELISA.Infiltration of c-kit(+) cells in pulmonary arterial lesions was associated with an increase in c-kit mRNA expression (P < 0.01 compared with control subjects). Both c-kit(+)/tryptase(+) mast cells and c-kit(+)/tryptase(-) BM-derived cells were increased in pulmonary arteries of patients with IPAH compared with control subjects (106.6 ± 54.5 vs. 28 ± 16.8/mm(2) and 143.8 ± 101.1 vs. 23.3 ± 11.9/mm(2); all P<0.01). Plasma-soluble c-kit was increased in IPAH compared with control subjects (27.4 ± 12.4 vs. 19.5 ± 5.8 ng/ml; P<0.05). Two populations of circulating BM-derived cells (lin-CD34(high)CD133(high) [c-kit(high)CXCR4(low)] and lin-CD34(low)CD133(-) [c-kit(low)CXCR4(high)]) were increased in IPAH compared with control subjects (P=0.01). Pulmonary arterial lesions were associated with vasa vasorum expansion expressing CXL12/SDF-1α that may recruit c-kit(+) cells.In IPAH, c-kit(+) cells infiltrate pulmonary arterial lesions and may participate to vascular remodeling. Therefore, c-kit may represent a potential target for innovative PAH therapy.
Altered glycosylation of integrin adhesion molecules in colorectal cancer cells and decreased adhesion to the extracellular matrix.
Authors: B von Lampe, A Stallmach, E O Riecken
Journal: Gut (1993)

The integrin mediated interactions between tumour cells and the surrounding extracellular matrix are thought to play crucial parts in the complex process of invasion and metastasis. It has been previously shown that the expression of integrins is differently diminished in a chain-specific manner in human colorectal cancer. To further characterise the integrins still expressed in colorectal carcinomas, immunoblots with monoclonal antibodies against the beta 1 integrin subunit have been performed. In isolated cell membranes of colorectal cancers a second smaller beta 1 chain (105 kD non-reduced) was found as well as the mature beta 1 chain (116 kD non-reduced) present in normal mucosa of the colon. This smaller beta 1 chain comigrates with the diminished glycosylated precursor form of the beta 1 chain. The role of N-glycosylation for the function and expression of integrins in vitro was therefore investigated, with deoxymannojirimycin (DMJ) and deoxynojirimycin (DNJ) as specific inhibitors of N-glycan processing. Pretreatment of human colon adenocarcinoma derived HT-29 cells with DMJ resulted in an expression of the 105 kD beta 1 precursor chain and of smaller forms of the alpha 1, alpha 3, alpha 6, and alpha v integrin subunits in a time and dose dependent manner. HT-29 cells treated with DMJ adhered poorly to laminin (8% of untreated controls), collagen type IV (40%), and fibronectin (35%). Pretreatment of the cells with DNJ did not alter the molecular weight of the integrin chains expressed and reduced HT-29 adhesion to laminin and fibronectin only to 68% and 49% respectively. Adhesion to collagen type IV was increased to 124% by DNJ. These results show that N-glycan processing is essential for the function and expression of integrins in human colorectal cancer cells. An altered glycosylation of these adhesion receptors may contribute to a more invasive or metastatic phenotype in colorectal cancer.
Biphasic Development of the Mammalian Ventricular Conduction System
Authors: Lucile Miquerol, Natividad Moreno-Rascon, Sabrina Beyer, Laurent Dupays, Sigolène M. Meilhac, Margaret E. Buckingham, Diego Franco, Robert G. Kelly
Journal: Circulation Research (2010)

The ventricular conduction system controls the propagation of electric activity through the heart to coordinate cardiac contraction. This system is composed of specialized cardiomyocytes organized in defined structures including central components and a peripheral Purkinje fiber network. How the mammalian ventricular conduction system is established during development remains controversial.To define the lineage relationship between cells of the murine ventricular conduction system and surrounding working myocytes.A retrospective clonal analysis using the alpha-cardiac actin(nlaacZ/+) mouse line was carried out in three week old hearts. Clusters of clonally related myocytes were screened for conductive cells using connexin40-driven enhanced green fluorescent protein expression. Two classes of clusters containing conductive cells were obtained. Mixed clusters, composed of conductive and working myocytes, reveal that both cell types develop from common progenitor cells, whereas smaller unmixed clusters, composed exclusively of conductive cells, show that proliferation continues after lineage restriction to the conduction system lineage. Differences in the working component of mixed clusters between the right and left ventricles reveal distinct progenitor cell histories in these cardiac compartments. These results are supported by genetic fate mapping using Cre recombinase revealing progressive restriction of connexin40-positive myocytes to a conductive fate.A biphasic mode of development, lineage restriction followed by limited outgrowth, underlies establishment of the mammalian ventricular conduction system.
Effectiveness of community case management of severe pneumonia with oral amoxicillin in children aged 2–59 months in Matiari district, rural Pakistan: a cluster-randomised controlled trial
Authors: Sajid Soofi, Sheraz Ahmed, Matthew P Fox, William B MacLeod, Donald M Thea, Shamim A Qazi, Zulfiqar A Bhutta
Journal: The Lancet (2012)