tbuckley/cabot-search huggingface dataset:
Mixing old and young: enhancing rejuvenation and accelerating aging
Authors: Ashley Lau, Brian K. Kennedy, James L. Kirkland, Stefan G. Tullius
Journal: Journal of Clinical Investigation (2019)

Donor age and recipient age are factors that influence transplantation outcomes. Aside from age-associated differences in intrinsic graft function and alloimmune responses, the ability of young and old cells to exert either rejuvenating or aging effects extrinsically may also apply to the transplantation of hematopoietic stem cells or solid organ transplants. While the potential for rejuvenation mediated by the transfer of youthful cells is currently being explored for therapeutic applications, aspects that relate to accelerating aging are no less clinically significant. Those effects may be particularly relevant in transplantation with an age discrepancy between donor and recipient. Here, we review recent advances in understanding the mechanisms by which young and old cells modify their environments to promote rejuvenation- or aging-associated phenotypes. We discuss their relevance to clinical transplantation and highlight potential opportunities for therapeutic intervention.
Compensatory regulatory mechanisms that restore apoptosis following bcl-2 suppression.
Authors: Marvin Rubenstein, Courtney M.P. Hollowell, Patrick Guinan
Journal: Journal of Clinical Oncology (2014)

e13536 Background: Gene therapy, in theory, is specific. However, in practice, it encounters difficulties. In the apoptosis pathway there are many regulatory proteins which either promote or inhibit the process. Suppression of the apoptosis inhibitor bcl-2 has now reached clinical trials. Therefore, it's now important to identify effects upon non-targeted proteins which through altered expression may compensate and restore the apoptotic process. Antisense oligonucleotides (oligos) have targeted regulatory proteins in both in vivo and in vitro prostate cancer models. When directed against bcl-2 there is compensation involving increased expression of the androgen receptor and its p300 and IL-6 co-activators, potentially selecting a more aggressive, androgen sensitive phenotype. Methods: We evaluated mono- and bispecific oligos which targeted and equally suppressed bcl-2 expression in LNCaP cells. To further evaluate compensatory mechanisms related to tumor resistance we evaluated the level of additional regulators of apoptosis: bax, caspase-3, AKT-1 and STAT-3 employing RT-PCR and agarose gel quantification. Bands representing pcr product were photographed, converted to black and white and assessed by MIPAV software. Results: Comparable amounts of RNA from LNCaP cells treated with either mono- or bispecific oligos directed against bcl-2 were evaluated by RT-PCR using primers directed against bax, caspase-3, AKT-1 and STAT-3. When background intensity was subtracted, the relative intensity of bands corresponding to AKT-1 and STAT-3 (inhibitors of apoptosis) were significantly increased while caspase-3 (promoter of apoptosis) was significantly diminished. No change was found in bax (promoter of apoptosis) expression. Conclusions: These data suggest that bcl-2 suppression is accompanied by compensatory changes in the expression of non-targeted genes which may restore apoptosis and promote tumor resistance.
Contributing factors for diagnostic delays in advanced lung cancer (LC) patients and the role of multidisciplinary tumor board (MTB) discussion in a community hospital setting.
Authors: Rajitha Sunkara, Aixa Soyano, Samaan Rafeq, Leslie A. Martin, David Lee, Dorcas Chi
Journal: Journal of Clinical Oncology (2014)

e17592 Background: The median delay from symptoms to treatment initiation (TI) for LC patients is 3-6 months, which is a significant stressor for newly diagnosed. The contributing factors remain uncertain. Methods: We retrospectively reviewed small cell lung cancer (SCLC) and stage III/IV non small cell lung cancer (NSCLC) patients between 2009 and 2013 at St. Elizabeth Medical Center, Boston. We studied the lag periods from initial diagnostic imaging (IDI) with CT/MRI to TI for and investigated the underlying reasons. Time intervals were summarized using mean, standard deviation, median and IQR and compared between patient groups using t-test. Results: We identified 80 evaluable patients. Median interval from IDI to TI is 28 days (Table). PET/CT is identified as one of the modifiable contributing factors in metastatic disease. 52/80 had PET/CT for staging but only 5/52 (9%) had treatment change. 47/80 had IDI suggestive of metastases (SCLC and NSCLC). 30/47 had PET/CT for confirmation without change of treatment planning.The median delay from IDI to TI in 30/47 is 28 days compared to 13 days in the 17/47 without PET/CT (P=0.01). This delay is even higher for 8/30, who had additional biopsies after PET/CT at 58.5 days. 64/80 had MTB discussion. 56/64 had MTB before TI with a median interval of 19 days from IDI to MTB discussion. In these 56, the interval from IDI to TI was 33.5 days. Conclusions: Our data questions the role of PET/CT in patients, whose IDI supports metastases. Also there is a need for early utilization of MTB to optimally sequence the tests and avoid unnecessary delays. N Mean ± SD Median IQR T-test All patients 80 32.0 ± 21.8 28 15.5 - 47 Specialty Pulm 44 34.5 ± 20.2 30 21 - 46 IR/CT surgery 36 28.9 ± 23.5 23 9 – 48.5 P=0.2558 Inpatient vs. out Inpatient 45 23.8 ± 17.9 23 11 - 31 Outpatient 35 42.5 ± 22.2 40 23 - 58 P<0.0001 PET Y (before Tx) 52 38.2 ± 21.4 31 23 - 53 N (No or after Tx) 28 20.4 ± 17.9 15.5 5 – 29.5 P=0.0003 Type of cancer Non-small 62 35.3 ± 22.3 30 21 - 49 Small 18 20.7 ± 16.2 15.5 7 - 31 P=0.0119 For non-small CA Original stg 3 22 44.7 ± 18.9 39.5 30 - 52 Original stg 4 39 30.0 ± 22.8 25 13 - 47 P=0.0130 Final stg 3 20 46.0 ± 18.9 39.5 32 - 56.5 Final stg 4 42 30.2 ± 22.1 25.5 13 - 47 P=0.0080
Procedural Clinical Complications, Case-Fatality Risks, and Risk Factors in Endovascular and Neurosurgical Treatment of Unruptured Intracranial Aneurysms
Authors: Annemijn M. Algra, Antti Lindgren, Mervyn D. I. Vergouwen, Jacoba P. Greving, Irene C. van der Schaaf, Tristan P. C. van Doormaal, Gabriel J. E. Rinkel
Journal: JAMA Neurology (2018)

The risk of procedural clinical complications and the case-fatality rate (CFR) from preventive treatment of unruptured intracranial aneurysms varies between studies and may depend on treatment modality and risk factors.
Tofacitinib benefit‐risk profile in chronic plaque psoriasis
Authors: B.E. Strober, A.B. Gottlieb, P.C.M. Kerkhof, L. Puig, H. Bachelez, E. Chouela, S. Imafuku, D. Thaçi, H. Tan, H. Valdez, P. Gupta, M. Kaur, V. Frajzyngier, R. Wolk
Journal: British Journal of Dermatology (2019)

Although there are several highly effective treatments for severe psoriasis, many of them have to be given by injection and they are ineffective in some patients. Tofacitinib is a new oral (taken by mouth) drug which inhibits an enzyme, Janus kinase. It has proved beneficial in diseases called rheumatoid arthritis and ulcerative colitis, and its use has been studied in psoriasis. The authors, based in Europe, North and South America and Japan, have reviewed 6 clinical trials assessing the benefits and risks of tofacitinib treatment in patients with moderate or severe plaque psoriasis. The data collected comprise over 5,000 patient years. Patients received either 5mg or 10mg twice daily and were reviewed after 4 months and after a year. The drug was generally well tolerated, with side effects similar to the “biologic treatments” currently available for moderate to severe psoriasis, although there was a slightly higher rate of herpes zoster (shingles) infection, especially in the higher dose. The higher dose was more effective, and overall there was considerable improvement in the patient's quality of life, with improvement in the appearance of skin and nails and rapid reduction of itching. The authors conclude that the drug is effective and has an acceptable safety profile. As yet there is only one published trial comparing its efficacy with a biologic treatment (etanercept) and further comparisons with established drugs are desirable. However many patients would prefer to take a drug orally rather than by injection; injection reactions are a significant problem with biologic treatments.
A comparison of<i> epidermal growth factor receptor</i> (<i>EGFR</i>) mutation testing methods in different tissue types in non-small cell lung cancer.
Authors: Feng Guo
Journal: Journal of Clinical Oncology (2014)

e22128 Background: In contrast to well-understood significance of EGFR mutation detection in treatment decision-making, no consensus on which methodology for detecting mutations is preferable in clinical practice. The presence of false positives due to the technique carried out for mutation analysis influences an accurate estimation of EGFR-TKI response. False negatives directly exclude a potential application of an EGFR-TKI. Methods: EGFR mutations in individual sample types including pleural effusion, bronchoscopic biopsies, and surgical resections, were detected by three techniques with low or high sensitivity, including direct sequencing, ARMS, and HRM assay. Results: The corresponding activating EGFR mutation rates were 45.00%, 30.36%, and 42.86%, in pleural effuse, bronchoscopic biopsies, and surgical resections. The EGFR mutations were less frequently detected in bronchoscopic biopsies, irrelevant of which method was performed. However, ARMS were optimal owing to the small amounts of DNA prepared from biopsies. Cytology sample was a valuable alternative to traditional samples given that a sensitive method was performed. For surgical resections, the testing method could be decided based on every laboratory’s expertise, and direct sequencing was highly recommended. The discordance was 26.32% between direct sequencing and ARMS, and was 21.33% between direct sequencing and HRM. Conclusions: The choice of method was supposed to be decided according to sample type. Secondly, performing two methods (screening and targeted method) sequentially in clinical practice because of the presence of non-neglected discordance between any two methods due to their own benefits and drawbacks would be helpful.
Racism and Health: Evidence and Needed Research
Authors: David R. Williams, Jourdyn A. Lawrence, Brigette A. Davis
Journal: Annual Review of Public Health (2019)

In recent decades, there has been remarkable growth in scientific research examining the multiple ways in which racism can adversely affect health. This interest has been driven in part by the striking persistence of racial/ethnic inequities in health and the empirical evidence that indicates that socioeconomic factors alone do not account for racial/ethnic inequities in health. Racism is considered a fundamental cause of adverse health outcomes for racial/ethnic minorities and racial/ethnic inequities in health. This article provides an overview of the evidence linking the primary domains of racism-structural racism, cultural racism, and individual-level discrimination-to mental and physical health outcomes. For each mechanism, we describe key findings and identify priorities for future research. We also discuss evidence for interventions to reduce racism and describe research needed to advance knowledge in this area.
Durable Responses with Pembrolizumab in Relapsed/Refractory Mycosis Fungoides and Sézary Syndrome: Final Results from a Phase 2 Multicenter Study
Authors: Michael S Khodadoust, Alain Rook, Pierluigi Porcu, Francine M. Foss, Alison J. Moskowitz, Andrei R. Shustov, Satish Shanbhag, Lubomir Sokol, Steven P Fling, Shufeng Li, Asa Davis, Sophia Fong, Jinah Kim, Yi Yang, Jennifer H Yearley, Priyanka B Subrahmanyam, Holden T. Maecker, Yelena Budovskaya, Biswajit Das, Rajesh Patidar, Vivekananda Datta, Chris Karlovich, Steven M. Horwitz, Elad Sharon, Holbrook Kohrt, Martin A Cheever, Youn H. Kim
Journal: Blood (2018)
Adjuvant chemoradiotherapy with infusional fluorouracil in high-risk adenocarcinoma of the stomach or gastroesophageal junction.
Authors: Maria Vieito, Nieves Martinez Lago, Rafael Varela Ponte, Yolanda Vidal, Sonia Candamio, Francisca Vazquez, Rafael Lopez, Carmela Rodriguez
Journal: Journal of Clinical Oncology (2014)

e15068 Background: Adjuvant radio-chemotherapy with 5- FU bolus, McDonald regime is the standard adjuvant treatment due to it has shown significant benefit in OS and DFS over surgery alone at a non-negligible toxicity´s expense. We explore efficacy and toxicity of a modified 5Fu continuous infusion scheme. Methods: Retrospective study including patients diagnosed as gastric adenocarcinoma / GEJ with R0 resection, PS 0-2, stage IB-IIIC between 2007 and august 2012. 5FUm schedule consisting in 400 mg/m2 iv bolus 5-FU with leucovorin 200 mg iv and 1200 mg/m2 in 46-hour infusion for 4 infusions before and 4 after radiotherapy. During radiotherapy (45 Gy) received 5-FU CI 225 mg/m2/day. Outcomes evaluated were feasibility, toxicity, disease free survival and overall survival. Results: The baseline characteristics of the patients appear in the following data: Characteristics N Age Median (range) 63 (40-78) Sex Male / Female 40 / 18 ECOG PS 0 /1 / 2 13 / 43 / 2 Histologic Type Intestinal / Difusse / Unknow 27 / 19 / 12 Grade Well / Moderate / Poor / undifferentiated / Unknow 6 / 24 / 17 / 2 / 9 Stage IB / IIA / IIB / IIIA / IIIB / IIIC 4 / 12 / 17 / 10 / 14 / 1 Linfadenecty D 0 - 1 / D 2 41 / 17 Nº of lymphadenopathy < 15 / > 15 13 / 45 Invasion Vascular / Perineural / No / Unknow 30 / 31 / 15 / 12 Margins R0 / R1 56 / 2 Patients received a mean of 1.63 cycle pre and 1.78 cycle post radiotherapy. The median radiotherapy dose was 44.83 Gy, 4.69 weeks of concomitant chemotherapy. Dose intensity was 99.6%, 95,4% and 89.9% respectively. We observed the following grade III-IV toxicities: neutropenia 8.6%, mucositis 8.6, vomiting 8,6%, EPP, 5,2% and diarrhea 5.2%. After a median follow up of 53 months, 20 deaths and 25 recurrences have occurred giving us a median OS of 59 months,( 3 year Os of65%) and a median DFS of 55,8 months (3 year DFS 60%). Variables correlated with a worse outcome were microscopically positive margins, locally advanced disease (T>2, N+), linfovascular o perineural invasion and a lymphadenectomy with less than 14 lymph nodes examined. Conclusions: Our infusion 5Fu regime is feasible in terms of dose intensity, has an acceptable rate of grade 3-4 toxicity and produces comparable results to bolus 5Fu in terms of survival.
Risk factors for oral lesions and septicemia associated in children with acute lymphoblastic leukemia in chemotherapy.
Authors: Araceli Castellanos-Toledo, Rosaura Idania Gutierrez-Vargas, Yuri Igor Lopez-Carrera, Javier Portilla-Robertson, Armando Martinez-Avalos, Jose de Jesus Figueroa Carbajal
Journal: Journal of Clinical Oncology (2014)

e21003 Background: In acute lymphoblastic leukemia (ALL), are described lesions in the oral cavity being the most frequent oral mucositis after chemotherapy, due to the lack of selectivity towards cells with high replication rate as the oral mucosa, implying a risk for local and systemic infections in patients with neutropenic status. Objective: To determine the risk factors for develop oral lesions (mucositis and infections) in children with ALL and high-dose chemotherapy and whether these injuries are associated with septicemia. Methods: Prospective and longitudinal study in children younger 18 years old with ALL and no prior treatment, included in an intensive chemotherapy regimen. Sample size: The total available for 2012-2013. Risk factors analyzed: age, sex, malnutrition, neutropenia, oral hygiene and bacteremia associated with oral lesions. Statistics analysis: Measurements of frequency, bivariate analysis with Fisher´s exact test and relative-risk (RR) to oral lesions and septicemia. Results: 17 children were included (2-16 years old), 71% developed oral lesion, 65% oral mucositis, 29% oral bacterial infection and 12% candidiasis; 24 mouth secretion cultures were performed, 19 were positive to Gram-positive and Gram-negative pathogens and one KOH to Candida albicans. The risk factors associated with oral mucositis grade 3 and 4, were malnutrition ≥2 weeks (RR 2.66, 95% CI 1.06 - 2.50, p=0.009), severe neutropenia ≥4 weeks (RR 2.00, 95% CI 1.07 – 3.71, p=0.044) and a poor oral hygiene ≥4 weeks (RR 4.50, 95% CI 1.33 -15. 38, p= 0.021). The relative-risk for oral lesions associated to septicemia was 2.10, p=0.101, although no statistical significance was found, this represented a RR tendency for clinic systemic infections in 24% of cases with associated morbidity and mortality. Conclusions: High-dose chemotherapy-induced oral mucositis was the most common oral lesion and was associated to malnutrition, severe neutropenia and poor oral hygiene, with a close tendency to develop bacteremia to come from an oral lesion.
2-Deoxy-D-glucose: Old molecule, new brain tumor agent inducing autophagy
Authors: Waldemar Priebe, Timothy Madden, Conrad Charles, Yongjie Ji, Sigmond Hsu, Izabela Fokt, Frederick Lang
Journal: Cancer Research (2007)

4863  Prevalent changes that occur with the progression of brain tumors include activation of survival pathways and a number of adaptive changes that incorporate a metabolic shift that promote activation of glycolysis, preferentially. Additionally, poorly perfused tumors that become regionally hypoxic also stimulate signaling pathways to up-regulate angiogenesis and shift metabolism to preferentially utilize glycolysis. We postulated that because of these features, gliomas represent a unique disease state that will be particularly sensitive to inhibitors of glycolysis that can deprive tumor cells of glucose derived energy and induce autophagy. To test this hypothesis we have used 2-deoxy-D-glucose (2-DG), a known glycolytic inhibitor, against a number of glioma cell line panels in vitro in both hypoxic and normoxic conditions. 2-DG inhibited glioblastoma cells grown under both conditions at 2-6 mM; these concentrationsare achievable in vivo. Most interestingly, 2-DG potently induces autophagic cell death at 2 mM concentrations in two tested gliomblastoma cell lines (U87 and D54). Subsequently, animals containing orthotopic glioma xenografts were used in dose response studies to confirm, in vivo, activity we observed in vitro. Our studies demonstrated that 2-DG administered orally demonstrated significant antitumor activity. Surprisingly, 2-DG was equally effective in animal survival gains as the positive control used, temozolomide, a drug which is a standard care therapy for brain tumors. This therapy was also well tolerated in vivo with animals showing no evidence of toxicity. These findings are very promising and warrant further preclinical evaluation of 2-DG as well as studies aimed at the design and synthesis of new inhibitors of glycolysis.
The scope of NGS testing: A study of ERBB2 and BRAF.
Authors: Sheryl Krevsky Elkin, Linda M. Call, Jennifer Carter
Journal: Journal of Clinical Oncology (2014)

e22103 Background: Increased use of companion diagnostic testing has allowed greater detection of targetable mutations in selected tumor types. Next-generation DNA sequencing (NGS) allows broader testing that may reveal targetable mutations in more patients. Methods: Through N-of-One’s clinical interpretation service, we have accumulated a dataset of over 5,000 sequenced tumors. We examined the incidence of ERBB2 and BRAF alterations. Results: ERBB2 amplification is most frequently reported in breast and gastric cancer; however, ERBB2 alterations have been observed in other cancer types. In our dataset, ERBB2 amplification was detected in 11% (50/439) of breast carcinomas and in 8% (8/104) of gastric adenocarcinomas, but also in 15% (9/59) of esophageal adenocarcinomas, 8% (4/51) of endometrial adenocarcinomas, and smaller percentages of urothelial carcinoma, colorectal carcinoma, and lung adenocarcinoma. Activating mutations in ERBB2 have been reported in both lung and breast cancer; in our dataset, we identified ERBB2 mutations in 4% (17/386) of lung adenocarcinomas and 3% (14/439) of breast carcinomas, but also in a number of other tumor types. Our dataset included 176 tumors containing 184 BRAF alterations. V600E mutations represent less than 50% of the total BRAF mutations (78/184), and V600E accounts for less than 50% of BRAF mutations in individual tumor types such as melanoma (13/33, n=101), lung adenocarcinoma (6/15, n=380), and carcinoma of unknown primary (5/11, n=223). V600E mutations were more prevalent in colorectal cancer (13/18, n=264) and papillary thyroid carcinoma (10/10, n=15). Among the non-V600 mutations, we observed 12 “reduced activity” mutations at codon D594 and 32 mutations in the “G-loop” at codons G464, G466, and G469. BRAF amplifications represented 11% (21/184) of BRAF alterations, and rearrangements represented 8% (15/184) of BRAF alterations. Conclusions: NGS testing has facilitated identification of ERBB2 alterations across a broader range of tumor types, as well as the observation of a sizable subset of non-V600E BRAF mutations. These observations have implications for the application of diagnostic testing and therapy, and may have potential as hypothesis-generating resources for clinical trials and drug development.
Continuous sequential chemotherapy for advanced testicular cancer: Japanese high-volume center experience.
Authors: Terukazu Nakamura, Takashi Ueda, Masakatsu Oishi, Fumiya Hongo, Yoshio Naya, Hiroyuki Nakanishi, Kazumi Kamoi, Koji Okihara, Tsuneharu Miki
Journal: Journal of Clinical Oncology (2014)

e15618 Background: Chemotherapy- refractory or resistant GCTs, so called ‘difficult-to-treat’ GCTs would remain continuously disease-free with salvage chemotherapy or surgery. The optimal salvage chemotherapy remains unclear. The aim of this study was to assess the efficacy of ‘sequential’ chemotherapy for advanced testicular cancer. Methods: Two hundreds and fifty-two patients with advanced GCTs treated at Kyoto Prefectural University of Medicine from June, 1998 to December, 2012 were retrospectively assessed. Results: Median age was 32 year-old (range:17-68y.o.). Non-seminoma was in 203 cases (80.6%). IGCCC showed good in 110 cases (43.7%), intermediate 65 (25.8%), poor 61 (24.2%). The summary of chemotherapy sequence was showed in the Table. Five-year overall survival rate stratified by chemotherapy line was 88.5% in 2nd line, 78.8% in 3rd line and 56.7% in 4th line or more, respectively. Five-year overall survival stratified by IGCCC of all cases was 88.2% in good prognosis, 76.4% in intermediate prognosis and 66.9% in poor prognosis, respectively. In the cases with salvage chemotherapy group, 5-year overall survival was 76.6% in good, 61.9% in intermediate and 63.7% in poor, respectively. Clinical outcomes showed no evidence of disease (NED) was obtained in 93.6% and 86.1% with induction and second line therapy, respectively. Noteworthy mentioned, about 40% patients had NED even in the 4thline or more chemotherapy group. Conclusions: Very good and relatively good prognosis was obtained in the patients with induction and salvage chemotherapy at Japanese high volume center, respectively. Sequential continuous chemotherapy would be very important to manage ‘difficult-to-treat’ advanced germ cell tumors. Chemotherapy line (n) 1st line (252) 2nd line (141) 3rd line (101) 4th line (72) 5th line (44) 6th line (28) BEP+EP 232 16 3 1 1 - PVB 3 - - - - - VIP+VeIP 6 44 12 3 1 - HDCT 7 11 2 2 - - TIP+TIN - 58 53 25 17 11 IrP+IrN - 8 18 20 12 7 TGP+TGN - 2 6 14 6 6 Others 3 2 6 7 7 4 Additional procedure RPLND 158, ExRPLN resection 103, EBRT 49, RFA 25