tbuckley/cabot-search huggingface dataset:
A phase 1 study of daily oral perifosine (P) with weekly paclitaxel (T)
Authors: B. Ebrahimi, J. J. Nemunaitis, R. Shiffman, R. Birch, M. Diaz-Lacayo, D. H. Berdeaux, M. A. Rettenmaier, T. F. Goggins, I. C. Henderson
Journal: Journal of Clinical Oncology (2006)

13117 Background: P is an oral signal transduction modulator with limited toxicity. P combined with 3-weekly T led to no toxicity beyond that expected with each drug alone. Weekly T is more effective than 3-weekly T in some settings (Seidman, ASCO 2004:512), so this study evaluated whether weekly T altered the tolerance to P. Methods: Twelve patients (pts) were enrolled. T was given at 80 mg/m 2 on days 1, 8 and 15 of a 28 day cycle. P, 50 mg, was given 1, 2 or 3 times a day on days 1–21 of each cycle. Results: Tumor types were lung 2, breast 4, endometrium 3 and other 3. Median age was 55 (range 41–82). All pts had received prior chemotherapy (median 2.5, range 1–3 regimens) and 6 a prior taxane. Three pts were entered at each dose and the cohort expanded to 6 pts if 2 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during cycle 1. A dose was toxic if 4 or more pts experienced a DLT during cycle 1. Since toxicity was not dose limiting in any cohort, the 150 dose was expanded to 6 pts. There were no grade 3/4 hematologic toxicities. The grade 3/4 non-hematologic toxicities at least possibly related to perifosine are given in the table below: The high glucose values were 276 and 277. A total of 38 cycles and a median of 2.5 cycles per pt (range 1–10+) were delivered. Full dose T was given in 85% of cycles (50 mg–100%, 100 mg–85%, 150 mg–86%). Dose reductions of T in 3 pts were related to neuropathy, suspected bronchitis and fatigue. One pt treated at 100 mg requested T be stopped after 6 cycles due to neurotoxicity and has received 6 additional cycles of perifosine alone. Perifosine dose reductions were required in 13% of cycles (50 mg - 0%, 100 mg - 21%, 150 mg - 9%). One pt each was reduced due to constipation, nausea and diarrhea. Five of 7 evaluable pts had stable disease (breast 2, cervix, endometrium, thyroid) for at least 3 months. Four remain stable at 3+ to 10+ months. Conclusions: The single agent doses of P (150 mg daily) &amp; T (80 mg/m 2 weekly) were given without increasing the toxicities expected from using each drug alone. Phase II studies are warranted to define the activity of the combination. [Table: see text] [Table: see text]
Abstract #2967: Inhibition of macrophage migration inhibitory factor (MIF) expression by dietary components in colorectal cancer cells
Authors: Haiyun Deng, Bryan Green, T. S. Ravikumar, Weng-Lang Yang
Journal: Cancer Research (2009)

It has been recognized that patients with inflammatory bowel disease (IBD) have increased risk of developing colon cancer. The consumption of dietary bioactive components that possess anti-inflammatory and anti-tumorigenic effects should be a suitable cancer prevention strategy for this patient group. MIF, a known pro-inflammatory cytokine, is one of the molecules that have been identified to have a dual activity in inflammation and tumorigenesis. Moreover, elevated levels of MIF in tissues and serum have been correlated with patients with IBD and colorectal cancer. In this study, we examined whether MIF was a molecular target of dietary components. Four dietary compounds, curcumin, quercetin, resveratrol, and sodium butyrate, were used to treat four human colorectal cancer cell lines, including HCT116, HT29, SW480 and KM12. The cell proliferation of these four cell lines was inhibited by all dietary compounds in a dose-dependent manner, as determined by MTS assay. The protein expression of MIF was also decreased in a dose-dependent manner in these colorectal cancer cells after 48 h treatment of these dietary compounds, except quercetin, as determined by Western blotting. The reduction of MIF protein expression in HCT116 and SW480 cells was not observed until 48 h and 72 h treatment of sodium butyrate. The mRNA level of MIF, as determined by semi-quantitative RT-PCR analysis, was also decreased in a dose-dependent manner after 48 h treatment of sodium butyrate in HCT116 cells. The mRNA level of MIF was decreased in 24 h in HCT116 and SW480 cells treated with sodium butyrate. In a MIF mRNA stability assay, addition of sodium butyrate didn\#8217;t change the MIF mRNA levels in actinomycin D-treated HCT116 cells, indicating that the reduction of MIF expression of sodium butyrate is regulated at the transcriptional level. Taken together, our results clearly demonstrate that dietary components can effectively inhibit MIF expression in colorectal cancer cells, along with evidence that MIF activity plays a role in the development of IBD and progression of colorectal cancer will lead a new strategy of targeting MIF for colorectal cancer prevention.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2967.
The impact of the number of lymph node metastases on the overall recurrence of colon cancer in the era of sentinel lymph node mapping
Authors: M. L. Arora, S. Saha, S. Sirop, B. Chakravarty, A. Korant, M. Soni, D. Wiese, D. Desai, B. Ganatra, S. Kaushal, D. Iddings
Journal: Journal of Clinical Oncology (2009)

4049 Background: Sentinel Lymph Node Mapping (SLNM) in colon Cancerc (Cca) has been shown to be successful, sensitive and accurate. We aimed to evaluate the recurrence rates in patients(pts) with Cca after SLNM and correlate it to the number of positive(+ve) LNs. Methods: Between 1996 and 2006, pts diagnosed with Cca were enrolled in a prospective trial and underwent SLNM and oncologic resection including regional LNs. The primary outcome was development of recurrence with minimum follow-up (f/u) of 24 months. For recurrence analysis, exclusion criteria included: stage IV disease, benign pathology, lost to follow-up, refusal of indicated chemotherapy, non cancer related death or second cancer. A retrospective matched control (diagnosed with Cca undergoing standard colon resection without SLNM, gp B) from our own institution were analyzed and compared to the SLNM group for the same period. Results: A total of 486 pts with Cca were included. Of these, 272 consecutive pts underwent SLNM between 1996–2006. SLNM was successful in 99.8% of pts, with a sensitivity, negative (-ve) predictive value, and overall accuracy of 85.3%, 91.7% and 94.4% respectively. The nodal positivity was 46.0%; of these, 15.1% had micrometastasis. The average number of LNs resected / pt was 15.0 and the average number of SLNs / pt was 2.4. For recurrence analysis, 153/272 pts with minimum f/u 2 years were included. Of these, 49 had stage I, 46 had stage II and 58 had stage III disease. The recurrence rates were 4.1%, 8.6% and 15.5% in stage I, II, and III disease respectively. The recurrence rates were significantly lower when our 153 pts were compared to 214 matched controls ( table 1 ). The recurrence rates increased from 6.3% in pts with no +ve LNs to 11.5% when one LN was +ve, 16.7% when 2 LNs were +ve and 20% when 3 or more LNs were +ve. Conclusions: SLNM in Cca is associated with decreased rates of recurrence as compared to conventional therapy. The number of positive LNs is an independent risk factor for recurrence. [Table: see text] No significant financial relationships to disclose.
A Novel Role for GATA3 in Mesangial Cells in Glomerular Development and Injury
Authors: Irina V. Grigorieva, Andre Oszwald, Elena F. Grigorieva, Helga Schachner, Barbara Neudert, Tammo Ostendorf, Jürgen Floege, Maja T. Lindenmeyer, Clemens D. Cohen, Ulf Panzer, Christof Aigner, Alice Schmidt, Frank Grosveld, Rajesh V. Thakker, Andrew Jackson Rees, Renate Kain
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Mesangial cells play a crucial role in maintaining glomerular homeostasis and injuries to these cells often result in progression to CKD like IgA and diabetic nephropathies. However, the transcription factors involved in mesangial cell development and function are largely unknown. The authors describe the role transcription factor GATA3 plays in mesangial cells in embryonic kidneys and healthy and injured adult glomeruli. Mice with haploinsufficiency of GATA3 have too few MC precursor cells and glomerular abnormalities. GATA3 expression increases in mesangial cells in mesangial proliferative GN in humans and rodent models suggesting GATA3 is important for glomerular homeostasis and response to injury. GATA3 also may be a useful a nuclear marker of human mesangial cells. Background GATA3 is a dual-zinc finger transcription factor that regulates gene expression in many developing tissues. In the kidney, GATA3 is essential for ureteric bud branching, and mice without it fail to develop kidneys. In humans, autosomal dominant GATA3 mutations can cause renal aplasia as part of the hypoparathyroidism, renal dysplasia, deafness (HDR) syndrome that includes mesangioproliferative GN. This suggests that GATA3 may have a previously unrecognized role in glomerular development or injury. Methods To determine GATA3’s role in glomerular development or injury, we assessed GATA3 expression in developing and mature kidneys from Gata3 heterozygous ( + /−) knockout mice, as well as injured human and rodent kidneys. Results We show that GATA3 is expressed by FOXD1 lineage stromal progenitor cells, and a subset of these cells mature into mesangial cells (MCs) that continue to express GATA3 in adult kidneys. In mice, we uncover that GATA3 is essential for normal glomerular development, and mice with haploinsufficiency of Gata3 have too few MC precursors and glomerular abnormalities. Expression of GATA3 is maintained in MCs of adult kidneys and is markedly increased in rodent models of mesangioproliferative GN and in IgA nephropathy, suggesting that GATA3 plays a critical role in the maintenance of glomerular homeostasis. Conclusions These results provide new insights on the role GATA3 plays in MC development and response to injury. It also shows that GATA3 may be a novel and robust nuclear marker for identifying MCs in tissue sections.
Assessment and Treatment of Patients With Type 2 Myocardial Infarction and Acute Nonischemic Myocardial Injury
Authors: Andrew P. DeFilippis, Andrew R. Chapman, Nicholas L. Mills, James A. de Lemos, Armin Arbab-Zadeh, L. Kristin Newby, David A. Morrow
Journal: Circulation (2019)

Although coronary thrombus overlying a disrupted atherosclerotic plaque has long been considered the hallmark and the primary therapeutic target for acute myocardial infarction (MI), multiple other mechanisms are now known to cause or contribute to MI. It is further recognized that an MI is just one of many types of acute myocardial injury. The Fourth Universal Definition of Myocardial Infarction provides a taxonomy for acute myocardial injury, including 5 subtypes of MI and nonischemic myocardial injury. The diagnosis of MI is reserved for patients with myocardial ischemia as the cause of myocardial injury, whether attributable to acute atherothrombosis (type 1 MI) or supply/demand mismatch without acute atherothrombosis (type 2 MI). Myocardial injury in the absence of ischemia is categorized as acute or chronic nonischemic myocardial injury. However, optimal evaluation and treatment strategies for these etiologically distinct diagnoses have yet to be defined. Herein, we review the epidemiology, risk factor associations, and diagnostic tools that may assist in differentiating between nonischemic myocardial injury, type 1 MI, and type 2 MI. We identify limitations, review new research, and propose a framework for the diagnostic and therapeutic approach for patients who have suspected MI or other causes of myocardial injury.
Usefulness and faults of the sentinel lymph node biopsy using dye technique in distal gastrectomy for gastric cancer
Authors: Y. Rino, N. Yukawa, H. Murakami, M. Masuda, T. Oshima, T. Sato, N. Yamamoto, T. Imada
Journal: Journal of Clinical Oncology (2009)

e15509 Background: We apply sentinel node biopsy (SNB) in distal gastrectomy to perform it as safe limited surgery. Limited surgery is a procedure in which the extent of lesion resection and lymph node dissection is reduced. We assessed usefulness and faults of intraoperative diagnosis of lymph node metastasis in this regard. Methods: Surgical procedures: Patent blue (1%) is injected submucosally into 4 to 5 different sites at 1 mL per site around the primary tumor. If blue nodes are found, biopsy and diagnosis of metastasis are performed at this point. Subjects and methods: The study was conducted in 96 gastric cancer patients with a preoperative diagnosis of T1 or mp invasion. Informed consent was obtained from the all patients. There were 65 males and 31 females with a mean age of 64.2 years. Tumor invasion of m, sm, mp, ss, and se was identified in 44, 38, 8, 2, and 4 patients, respectively. All patients underwent open distal gastrectomy (DG) (n=31) or laparoscopy-assisted distal gastrectomy (LADG) (n=65) and Billroth-I reconstruction. Results: The mean number of BNs dissected was 4.5 and 3.7 in DG and LADG cases, respectively. Intraoperative identification and biopsy of BNs could be performed in 34 of 35 DG patients and in 58 of 61 LADG patients. Of the 34 patients in whom BNs were identified, 5 had metastases in BNs confirmed by intraoperative frozen section diagnosis in DG cases. On the other hand, of the 58 LADG patients in whom BNs were identified, 5 had metastases in BNs confirmed by intraoperative frozen section diagnosis in LADG case. False-negative rate was 1.9%. Conclusions: SNB can be performed in LADG as well as in DG. For the case that shows infiltration up to MP, the possibility of lymph node metastasis for other lymph node is considered to be negligible. In obese cases we had some cases of no BNs and false-negative. In consequence, as long as the infiltration is lower than MP, and confirmed that metastasis was not found by blue node biopsy, distal gastrectomy using limited surgery would be thought to be done safely. No significant financial relationships to disclose.
NM23-H1 suppresses progression to the metastatic phenotype
Authors: Marian Novak, Qingbei Zhang, David Kaetzel
Journal: Cancer Research (2008)

330  NM23-H1 represents the first metastasis suppressor, identified by the virtue of its decreased expression in numerous metastatic cell lines. Three enzymatic activities have been identified with the protein in vitro, including NDP kinase, histidine kinase and 3’-5’ exonuclease functions, but their relative contributions to metastasis suppression remains unknown. The NDPK and 3’-5’ exonuclease activities suggest a novel antimutator function that resists genetic progression of cancer to metastatic forms. To test this hypothesis, a panel of NM23-H1 mutants with selective lesions in the three enzymatic activities has been developed and overexpressed by stable transfection in the non-metastatic (vertical growth phase) melanoma cell line WM793. The WM793 cell line panel was subjected to maintenance in protein-free medium to select for growth factor-independent proliferation, a common hallmark of metastatic progression. Forced expression of wild-type NM23-H1 significantly inhibited acquisition of the growth factor-independent phenotype relative to the parent WM793 over the course of a 4-5 month selection period. In contrast, a substitution mutation at lysine-12 (K12Q) which ablates all three enzymatic activities resulted in loss of the inhibitory activity. Also exhibiting loses in inhibitory activity were the mutants E5A, which is defective in 3’-5’ exonuclease activity, and H118F, which is both NDP kinase- and histidine kinase-deficient but possesses intact 3’-5’ exonuclease activity. Selection for growth factor-independent growth in the presence of forced expression of wild-type NM23-H1 yielded cells with negligible metastatic activity in athymic nude mice compared to those obtained with selected parent WM793 cells. These findings provide evidence for a novel role of NM23-H1 in suppressing the progression toward the metastatic phenotype. Studies are currently underway to assess the in vivo metastatic activity of the selectively disrupted functional mutants.
FRI0203 Pulmonary involvement in juvenile scleroderma
Authors: AM Romicka, A Malinowski
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Scleroderma in children manifests more frequently in the form of localised disease than syptemic one. This disorder is characterised by the presence of hard and tight skin (linear, localised and generalised morphea); systemic sclerosis, besides the skin changes it manifests the internal organ involvement. <h3>Objectives</h3> The aim of this report was an assessment of the frequency and nature of lung lesions in children with scleroderma. <h3>Methods</h3> The study comprised 32 non selected pts, aged from 4 to 18 yrs., 16 suffering from localised and 16 from systemic scleroderma. The disease duration ranged from 6 months to 14 yrs. The relation between clinical symptoms, x – ray findings and functional pulmonary tests were performed. <h3>Results</h3> Clinical and/or radiological signs (cought, dyspnoe, interstitial thickening) were found in 9 pts. The results of the functional investigation showed an impairment of the pulmonary function in 80.6% of pts with systemic sclerosis and 50% – with localised scleroderma, (total 65.6%). A decrease in DLCO (in 1/3 of pts in association with restrictive ventilatory failure) belonged to the most frequent of the lung damages. <h3>Conclusion</h3> Pulmonary involvement is frequent, however not a main feature in the course juvenile scleroderma. Abnormalities in functional tests were often the only manifestation of the respiratory sys-tem involvement. Lung functional disturbances may be independent of clinical features, muscular on skin involvement. Respiratory functional tests are helpful in estimation of systemic scleroderma in the cases manifesting only the clinical form of localised one. <h3>References</h3> Chomette G, Tranbaloc P, Beaufils H, <i>et al</i>. Les sclerodermies viscerales. Ann Med Interne (Paris) 1984;135:606 Greenwald GI, Tashkin DP, Gong H, <i>et al</i>. Longitudinal changes in lung function and respiratory symptoms in progressive systemic sclerosis. Am J Med. 1987;83:83 Lahman TJA. Systemic and localized scleroderma in children. Curr Opin Rheumatol. 1995;8:576 Uziel Y, Miller H, Lazar RM. Scleroderma in children. Pediatr Clin North Am. 1995;42:1171 Deheu I, Roujcan J-C, Cosnes A. Revuz: internal involvement in localized scleroderma. Medicine (Baltimore) 1994;73:241 Laxer RM, Feldman BM. General and local scleroderma in children and dermatomyositis and associated syndromes. Curr Opin Rheumatol. 1997;9:458
Geographic differences in breast cancer cases and controls by genetic and biological characteristics: explaining clustering of breast cancer at place of birth
Authors: Daikwon Han, Jo L. Freudenheim, Jing Nie, Matthew Bonner, Paola Muti, Maurizio Trevisan, Dominica Vito, Stephen Edge, Kate Luyegu, Peter Shields
Journal: Cancer Research (2005)

3214  There is growing evidence that early environmental exposures may be related to risk of breast cancer. We had identified previously geographic clustering of residences in early life, especially at birth, in relation to breast cancer risk. Because women with glutathione-S-transferase M1 (GSTM1) null genotypes may be more sensitive to environmental insults, we report here on clustering by GST genotype. Further, we examined whether there were differences by estrogen receptor (ER) or progesterone receptor (PR) status. We conducted a population-based case control study of incident, primary, histologically-confirmed breast cancer with controls frequency matched to cases on age, race and county of residence (the WEB study). All participants provided lifetime residential histories; we report here on place of birth. ER and PR status were obtained from medical records, and GST genotype was determined by PCR and agarose gel resolution. Geographic differences in clustering of breast cancer cases and controls were examined by the k-function method, a test for general tendency of spatial clustering, in groups stratified by GST genotype and by ER and PR status. We found evidence that breast cancer cases with GSTM1 null genotype were more clustered than controls, while there was no such evidence among GSTM1 wild genotype. However, there was no indication that cases with GSTM1 null genotype were more clustered when compared to cases with the wild genotype. We also observed a tendency to clustering among those with ER+ tumors relative to controls, but not among other groups defined by either ER or PR status. Clustering of women with GSTM1 null genotype may indicate that breast cancer cases with GSTM1 null genotype are more likely to share common environmental exposures at place of birth, but not necessarily congregated in a specific geographic area, and that such genetic susceptibility to early environmental exposure may play a role in subsequent risk of breast cancer. The tendency for clustering of ER positive tumors may also indicate that there are effects of common exogenous exposures related to place of birth among ER positive tumors. These findings are provocative in providing an indication that exogenous exposures at the time of birth may affect breast cancer risk.
Poly-TLR agonist polyantigenic vaccine cadi-05 in advanced nonsmall cell lung cancer
Authors: Bakulesh M. Khamar, Sur Pk, Dastidar Ag
Journal: Cancer Research (2006)

2905  Cadi-05 is a novel Poly-TLR, poly-antigenic vaccine containing Mycobacterium W. It is a potent Th1 response enhancer as revealed by cytokine profile. In a phase I study of patients with advanced non small cell lung cancer Stage IIIb or more, it was used along with chemotherapy and radiotherapy. Twnenty patients recruited were randomized to receive chemo-radio therapy (Control group) or chemo-radio therapy along with Cadi-05 (Treatment group). All the patients received External beam radiation therapy of 60 Gy in fraction of 2Gy, 5 fractions per week for six weeks. Chemotherapy used was cisplatin+ Etoposide. Cadi-05 was administered systemically by way of intradermal injections once every month for four months to this group. One patient in treatment group died while on therapy due to unrelated disease. Of nine patient in treatment group six responded to therapy. Six month after completion in the treatment group six who responded to therapy were found to have stable disease while all in the control arm had progression of the disease. Four of the six patients available for follow-up at eighteen months following therapy and demonstrated stable disease. Three years after therapy three patients of six responders are alive attending hospital. Cadi-05 used along with chemo-radiotherapy seems to provide a durable response. A phase two study is planned.