tbuckley/cabot-search huggingface dataset:
Treatment of breast, ovarian and lung cancer cells by inducing apoptosis with a deep eutectic solvent prepared from 2-deoxy-D-glucose and metformin: Cancer cell metabolism as a drug target.
Authors: Sauli Vuoti, Jaakko Eemil, Kumar Narasimha, Kai Reinikainen
Journal: Journal of Clinical Oncology (2020)

e15599 Background: Targeting cancer cell metabolism has gained attention as a future strategy to fight cancer. A characteristic of tumor cells is the elevated aerobic glycolysis for energy production. It has been shown that 2-deoxy-D-glucose (2DG) inhibits glycolysis and induces apoptotic cell death in different tumor types. The anti-diabetic drug metformin has been used in combination to enhance the inhibitory effect. So far, the attempts to combine both compounds in a clinical setting have been limited by the requirement of concentrations higher than those accessible in blood plasma of human beings. Deep eutectic solvents (DES) are solvent mixtures prepared from hydrogen bond donors and acceptors, wherein pharmaceutically active compounds can also be one of the components. Besides having unique physicochemical properties, DESs have been reported to demonstrate or enhance anticancer properties. Methods: We developed a DES mixture from 2DG and MET using a method based in mechanical grinding. We investigated the anticancer activity of conventional and DES mixtures of MET and 2DG, and used the mixtures to inhibit the growth, migration and invasion of cancer cells, and induce cell cycle arrest in vitro. Results: MET and 2DG, alone and in combination, induced apoptosis in the H460, SKOV-3, MDA-MB-231 and HCC1806 (TNBC) cell lines. Induction of apoptosis was further quantified by measurement of the loss of mitochondrial membrane potential and cleavage of PARP. DES mixtures had the highest impact on cell viability, exceeding the effect of 2DG/MET as single agents or combinations at all clinically relevant concentrations. The DES mixture with the lowest concentration to induce apoptosis consisted of 100 µM 2DG and 200 µM MET. A conventional solution with similar concentrations showed no activity. Conclusions: We developed a DES from 2DG/MET, which significantly reduced the viability of several types of cancer cells, surpassing the effect of single components or mixtures. The DES does not necessitate the use of additional solvents and could be used to develop clinical applications for targeting cancer cell metabolism.
Outcome of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy +/- intraoperative radiation therapy in the management of peritoneal sarcomatosis: Real world experience.
Authors: Ahmed ali Badran, Ahmed Elashwah, Mahmoud Abdelsatar Elshenawy, Ayman Azzam, Aisha Alshibani, Reem Alrakaf, Rania Naguib AbdelRehem, Abdelmoniem Eldali, Tarek Amin
Journal: Journal of Clinical Oncology (2020)

e23581 Background: Sarcomas are aggressive malignancy,30-40% of them originate from retroperitoneal space. which makes adequate free surgical margin after surgical debulking mostly not achievable. The addition of Hyperthermic intraperitoneal chemotherapy (HIPEC)+/- Intraoperative radiation therapy (IORT) may overcome local failure with an overall survival benefit. we studied the outcome of cytoreductive surgery (CRS)+ HIPEC +/- IORT on patients with peritoneal sarcomatosis,at our institute. Methods: Patients with peritoneal sarcomatosis treated with CRS+ HIPEC +/- IORT, in the period between 2011-2016 were included. Results: 24 patients identified;15(62.5%) were males. Median age was 58(31-77). Liposarcoma was the most frequent diagnosis in 50% of them. Neoadjuvant chemotherapy was received in 5 patients, while neoadjuvant radiation therapy was received in 3 patients. Cytoreduction completeness score (CC-0/1) was achieved in 19(79.17%), with median peritoneal cancer index (PCI) of 11 (3–28). Melphalan was the most commonly used agent for HIPEC chemotherapy, it was used in 16(66.67%) patients. IORT was given in 16(66.67%) patients. 8 patients developed grade III-IV Clavien-Dindo (CD) complications, with one died 5 days post operatively due to pulmonary embolism. Adjuvant chemotherapy was received in 9 patients. After a median follow up of 21 months, the mean, 2 years and estimated 4 years progression free survival was 19.6 months, 30.6% and 15.3% respectively, 13(54.2%) patients developed systemic progression, lung was the most affected site at time of progression in 8/13(61.5%) patients. Local progression occurred in two patients, while both systemic and local progression occurred in one patient. The 3 cases progressed locally underwent redo CRS and HIPEC with average 18 months between the first and redo surgery. The mean, 2 years and estimated 4 years overall survival was 21.2 months, 75.7% and 75.7% respective. In univariate analysis only CC score correlate with PFS, the mean PFS for those patients with CC (0-1) vs (2-3) was 13.7 vs 11.5 months ( p = 0.036). Conclusions: Addition of HIPEC+IORT to surgical debulking in the management of peritoneal sarcomatosis; seems to be safe and may improve local control rate with a questionable survival benefit, a larger cohort with a multicentric study is needed for further evaluation.
STAG2-mutated AML patients: ASXL1 cohesin binding motif status and mutation landscape.
Authors: Frank J Scarpa, Madhuri Paul, Wendy A Wolfson, Lawrence M. Weiss, Vincent Anthony Funari, Forrest Blocker
Journal: Journal of Clinical Oncology (2020)

7538 Background: ASXL1 and the cohesin complex ( STAG2, RAD21, SMC1A, and SMC3) are commonly mutated chromatin regulators with significant clinical implications in AML. The ASXL1-cohesin interactome regulates gene expression through chromatin accessibility via ASXL1’s cohesin binding motif (CBM). ASXL1 variants are most commonly located in the ASXM1 domain and onwards, and characteristically lead to loss of the PHD domain. Gain-of-functions in truncated ASXL1 are suggested to increase catalytic activity of BAP1, which binds the ASXH domain at AA 351, and to gain an interaction with BRD4, which binds somewhere between the ASXN and ASXH domains, to drive H3K4Me3 and H2AK119Ub. Methods: 2463 suspected AML patient bone marrow, peripheral blood, or FFPE tissue samples were evaluated using an all exon amplicon-based 27 gene NGS panel. Patients with a VAF &lt;10% in ASXL1 were excluded to avoid reporting artifacts, particularly in variant c. 1934dup. Statistics were performed using Fisher’s exact test. Results: Mutations in STAG2-mutated patients were enriched for sAML, as evidenced by the higher number of mutations in ASXL1, SRSF2, and BCOR (associated with sAML) compared to NPM1, DNMT3A, and PTPN11 (pAML). STAG2 mutations were found in 173 samples representing 93.5% of cohesin mutations. Of all ASXL1 mutations (VAF 10.1– 54.5%; median 32.2%) 4.0% occurred in the CBM. While 23.5% of samples with mutations outside ASXL1 CBM had concomitant mutations in STAG2, none of the 18 samples with CBM mutations (VAF 11.3 – 51.7%; median 42.5%) had any cohesin gene mutation (P = 0.0174). The proportion of BCOR (27.8% vs 9.2%; P = 0.024) and CEBPA (27.8% vs 8.2%; p = 0.016) mutated patients in the CBM+ group was significantly higher than the CBM- group. JAK2 (16.7% vs 5.4%), KRAS (22.2% vs 13.6%), EZH2 (22.2% vs 13.6%), and RUNX1 (38.9% vs 27.7%) mutations were also higher though not significantly in this group. Mutations throughout all of ASXL1, the 13 amino acids after the CBM, and hotspot variants all had STAG2 mutations at a frequency of 20.9-44.4%, further suggesting mutual exclusivity. Conclusions: STAG2 mutations and mutations in the CBM were mutually exclusive events and harbored different co-mutation frequencies. In compromised ASXL1 CBM cases, BCOR and CEBPA transcriptional regulators are significantly more mutated, but in cases of ASXL1 mutation outside the CBM, cohesin mutations are preferred, suggesting alternative chromatin accessibility mechanisms driving leukemogenesis. This observation has not been previously reported in the literature to our knowledge.
Complete human papillomavirus vaccination coverage over a 13-year period in a large population of privately insured U.S. patients.
Authors: Yull Edwin Arriaga, Bedda L Rosario, Elisabeth Scheufele, Amol Rajmane, Brett South, Sarah Kefayati, Judy George, Timothy Bullock, Gretchen Purcell Jackson, Kyu Rhee
Journal: Journal of Clinical Oncology (2020)

1511 Background: In the US, Human Papillomavirus (HPV) vaccination coverage is low, particularly in adolescents aged 13-15 years with respect to the Healthy People 2020 goal of 80%. There has been variability in the definition of measuring vaccination coverage in published studies. We examined complete HPV vaccination coverage in a population of privately insured individuals in the US. Methods: This retrospective study used IBM MarketScan Commercial Database, years 2006 to 2018. Inclusion criteria were ages 9 to 45 years and continuous enrollment from age 9 years or from 2006. Complete HPV vaccination coverage was defined as receipt of 2 doses (age 9-15 years) or 3 doses (age 16-45 years) within 12 months and stratified by year, demographics, and US region. Mean vaccination costs per dose were summarized by vaccine brand and health plan type. Results: The table summarizes complete HPV vaccination coverage by selected age groups for 2006 (n=12,221,938), 2010 (n=4,692,633), 2014 (n=2,808,132), and 2018 (n=1,662,148). From 2017 to 2018, the percentage of members who received HPV vaccine increased; for females ages 13-15 by 1% and 16-17 by 5% while for males ages 13-15 by 6% and 16-17 by 15%. In 2018, by region, the highest coverage was in females aged 18-26 at 53% and males aged 16-17 at 43% in the Northeast, and mean cost for each brand was $120 (-6% from 2017), $165 (-3%) and $220 (+5%) for Cervarix (n=151), Gardasil (n=8,201) and Gardasil 9 (n=139,356), respectively. The rate of utilization of Gardasil 9 increased from 33% (2015) to 94% (2018) of all vaccines. The lowest mean HPV vaccine cost by health plan type and brand was with Point-of-Service (POS) and Cervarix at $106, and the highest was with POS with Capitation and Gardasil 9 at $243. Conclusions: In a commercially insured US population, complete HPV vaccination coverage was lower than the Healthy People 2020 goal, but increased over time. Coverage varied according to health plan type and by region. In 2018, Gardasil 9 had the highest mean cost but was the most utilized vaccine, which may be related to broader coverage of HPV types. This study was limited by the transient nature of member enrollment and complexity of measuring complete vaccination coverage. These results should inform policy makers and practicing clinicians about the gap in vaccination coverage. [Table: see text]
Effects of cyclic and continuous nutrition infusion on serum nutritional indicators in patients with mechanical ventilated respiratory failure
Authors: Mian Zeng, Hui Yi, Gui-fang Lu, Yue Li, Hui Wang
Journal: BMJ (2011)

Objective To observe different effects of cyclic and continuous nutrition infusion on serum nutritional indicators, peripheral white blood cell counts (WBC), arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2) and acute physiology and chronic health evaluation Ⅲ (APACHE Ⅲ ) score in patients with mechanical ventilated respiratory failure (MVRF).Methods A cross-over and self-controlled trial was conducted in 48 patients with MVRF treated in a medical intensive care unit during December 2006 to June 2009, and continuous nutrition (group A) and cyclic nutrition (group B) were infused respectively for patients of the two groups.Serum levels of albumin (ALB), pre-albumin (PA), transferrin (TR), PaO2, PaCO2, WBC and APACHE Ⅲ score were measured for the patients with 24-hour continuous nutrition (group A) and 16-hour cyclic nutrition (group B)infusion.Effects of the two nutritional therapies were compared.Results After nutrition infusion, serum levels of ALB, PA and TR were (34±3)g/L, (196±28)mg/L and (2.1±0.3 ) g/L in group A, and (35 ±4) g/L, (198 ±25) mg/L and (2.0 ±0.4) g/L in group B, respectively; and PaO2 and PaCO2levels were (92 ± 12) mm Hg ( 1 mm Hg =0.133 kPa) and (42 ± 10) mm Hg in group A, and (91 ±9)mm Hg and (42 ± 10) mm Hg in group B, respectively.WBC and APACHE Ⅲ score were ( 11.8 ± 1.7) ×109/L and 38 ±7 in group A, and ( 12.6 ± 1.2) × 109/L and 40 ±6 in group B, respectively.Significant difference in serum levels of PA and TR was found between the two groups (PPA =0.019 and PTR =0.013),while there was no significant difference in other indictors between the two groups.Conclusions 24-hour continuous nutrition infusion for patients with MVRF can obviously improve their serum levels of PA and TR,but has no effect on serum level of ALB, PaO2, WBC and APACHE Ⅲ score in critical ill patients, as compared to those with 16-hour cyclic nutrition infusion.

Key words: 
Respiratory insufficiency;  Nutrition therapy;  Evaluation studies
Evidence for Exacerbation-Prone Asthma and Predictive Biomarkers of Exacerbation Frequency
Authors: Michael C. Peters, David Mauger, Kristie R. Ross, Brenda Phillips, Benjamin Gaston, Juan Carlos Cardet, Elliot Israel, Bruce D. Levy, Wanda Phipatanakul, Nizar N. Jarjour, Mario Castro, Sally E. Wenzel, Annette Hastie, Wendy Moore, Eugene Bleecker, John V. Fahy, Loren C. Denlinger
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Cross-sectional studies suggest an exacerbation-prone asthma (EPA) phenotype and the utility of blood eosinophils and plasma IL-6 as predictive biomarkers.Objectives: To prospectively test for EPA phenotype and utility of baseline blood measures of eosinophils and IL-6 as predictive biomarkers.Methods: Three-year asthma exacerbation data were analyzed in 406 adults in the Severe Asthma Research Program-3. Transition models were used to assess uninformed and informed probabilities of exacerbation in year 3. Binomial regression models were used to assess eosinophils and IL-6 as predictive biomarkers.Measurements and Main Results: Eighty-three participants (21%) had ≥1 exacerbation in each year (EPA) and 168 participants (41%) had no exacerbation in any year (exacerbation-resistant asthma). The uninformed probability of an exacerbation in Year 3 was 40%, but the informed probability increased to 63% with an exacerbation in Year 2 and 82% with an exacerbation in Years 1 and 2. The probability of a Year 3 exacerbation with no Year 1 or 2 exacerbations was 13%. Compared with exacerbation-resistant asthma, EPA was characterized by lower FEV1 and a higher prevalence of obesity, hypertension, and diabetes. High-plasma IL-6 occurred in EPA, and the incident rate ratio for exacerbation increased 10% for each 1-pg/μl increase in baseline IL-6 level. Although high blood eosinophils did not occur in EPA, the incident rate ratio for exacerbations increased 9% for each 100-cell/μl increase in baseline eosinophil number.Conclusions: Longitudinal analysis confirms an EPA phenotype characterized by features of metabolic dysfunction. Blood measures of IL-6, but not eosinophils, were significantly associated with EPA, and IL-6 and eosinophils predicted exacerbations in the sample as a whole.
子宫颈癌及其癌前病变的筛查
Authors: 胡尚英, 赵方辉
Journal: BMJ (2009)

宫颈癌是全球女性第二大恶性肿瘤.据估计,2002年全球有近50万新发病例和27万死亡病例;我国每年约有13.8万新发病例,5万死亡病例[1].我国第3次死因回顾抽样调查显示,全国宫颈癌的死亡率由20世纪70年代的11.35/10万下降至90年代的3.89/10万,再到本世纪初的2.86/10万,然而,中西部地区宫颈癌的死亡率仍居高不下[2].现将目前宫颈癌及癌前病变的筛查研究进展做一综述,以期更多的医生了解宫颈癌筛查相关知识,提高宫颈癌筛查覆盖面和防治水平。
Comparison of the training standards for general practitioners between China and UK
Authors: Jiang Yue
Journal: BMJ (2016)

对比中国《全科医师规范化培养标准(试行)》与英国皇家全科医学院《皇家全科医学院课程》，比较中英两国在全科医师培养标准上的特色，显示两国在全科医师培养标准的框架结构、培养目标、培养标准的主要内容和要求、轮转科室和时间等方面均存在差异。应加强国际交流与合作，从高等医学教育、全科医师规范化培训到毕业后的继续教育培训等多个方面借鉴英国的成功经验，建立适合中国国情具有全科医学特色的培训体系。
Dual but not single PD-1 or TIM-3 blockade enhances oncolytic virotherapy in refractory lung cancer
Authors: Fan Sun, Zong Sheng Guo, Alyssa D Gregory, Steven D Shapiro, Gutian Xiao, Zhaoxia Qu
Journal: Journal for ImmunoTherapy of Cancer (2020)

Programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade therapy fails in the majority of patients with cancer. Oncolytic viruses represent a new class of therapeutic agents, yet the therapeutic efficacy is still disappointing. Moreover, intratumoral injection of viruses is the main approach and preclinical studies mainly employ syngeneic or xenograft models.Use an endogenous mouse lung cancer model that faithfully recapitulates human lung cancer, and various in vivo, ex vivo and in vitro assays, to investigate the efficacy, mechanism of action and resistance of systemically administered oncolytic vaccinia virus (oVV), immunotherapy and their combination, to find an effective therapy for refractory lung cancer.Resembling human lung cancers, the majority of which are largely resistant to PD-1/PD-L1 blockade and with decreased PD-L1 expression and T-cell activation by our analysis, urethane-induced endogenous lung tumors in mice show reduced PD-L1 expression, low tumor-infiltrating lymphocytes and innate resistance to PD-1/PD-L1 blockade. Intravenous administration of oVV has efficacy and synergizes with simultaneous but not single blockade of PD-1 and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) in this cancer model. Besides direct tumor cell killing, oVV induces T-cell lung recruitment, tumor infiltration, along with expression of PD-1 and TIM-3 on T cells and PD-1 and TIM-3 ligands on tumor cells and tumor-associated immune cells. Blockade of PD-1 or TIM-3 also causes their mutual induction on T cells.While systemic administration of oVV shows efficacy in lung cancer by killing tumor cells directly and recruiting and activating T cells for indirect tumor killing, its induction of PD-1 and TIM-3 on T cells and PD-1 and TIM-3 ligands on tumors and tumor-associated immune cells as well as mutual induction of PD-1 or TIM-3 on T cells by their blockade restricts the efficacy of oVV or its combination with single PD-1 or TIM-3 blockade. The triple combination therapy is more effective for refractory lung cancer, and possibly other cold cancers as well.
浅析物理诊断的科研工作
Authors: 吴东, 朱峰
Journal: BMJ (2011)

随着医疗技术的快速发展,各类先进的检查设备不断应用,极大提高了临床诊治水平.但不可否认的是,传统的物理诊断仍然是临床实践的中心环节.无论是常见病、多发病还是疑难罕见病,病史和体检都是诊疗活动的第一步,是构建诊断大厦的基石.医生通过问病史和体检,了解病情梗概,大致估计鉴别诊断的范围,在此基础上有针对性地选择辅助检查,这是为长期临床实践所证明的合理的诊疗模式.社区的全科医师常年在基层工作,手边并无复杂精密的医疗设备可以借助,过硬的物理诊断本领就显得尤为重要[1]。
Comparison of efficacy and safety between negative pressure suction puncture and biopsy-gun puncture in ultrasound-guided percutaneous renal needle biopsy
Authors: Haifeng Yu, Huifei Shi, Haiping Xie, Jianyu Zhou, Cheng Feng, Yanfang Nie, Qiuyue Fu, Chunsheng Li
Journal: BMJ (2015)

Objective
To compare the efficacy and safety of different percutaneous renal needle biopsy methods.


Methods
Total 453 patients underwent renal needle biopsy in Taizhou Central Hospital during June 2009 and December 2014, including 221 patients received ultrasound-guided negative pressure suction puncture and 232 patients received ultrasound-guided biopsy gun puncture. The glomerular filtration rates (GFRs) were measured with single photon computed tomography [ECT (99mTc-DTPA)] before and after renal puncture. The amount of glomeruli obtained and incidence of perirenal hematoma were documented and compared between two groups.


Results
GFRs of punctured renal in negative pressure group were(37.7±11.6)ml/min before puncture and(38.3±11.7)ml/min after puncture (t=0.485, P=0.628); those in biopsy gun group were(36.8±11.3)ml/min before puncture and(37.4±11.9)ml/min after puncture (t=0.565, P=0.572). The incidence of perirenal hematoma >5 cm and ≤5 cm was 5.3%(24/453) and 6.0% (27/453), respectively. In hematoma >5cm group the GFR was decreased from(37.5±10.7)ml/min before renal puncture to(33.5±10.1)ml/min after puncture (t=2.103, P=0.038). The amount of glomeruli obtained by negative pressure puncture and by biopsy gun puncture was 26.4±15.9 and 20.6±9.9, respectively (t=4.648, P=0.000). The incidence of perirenal hematoma in negative pressure and biopsy gun groups was 6.8% (15/221) and 15.5% (36/232), respectively (χ2=8.634, P=0.003). The successful rate of renal needle biopsy in biopsy gun group was significant higher than that in negative pressure group [98.7±7.5% vs. 61.4±25.8%, t=5.453, P=0.000].


Conclusions
The large hematoma in punctured kidney would reduce the GFR in short-time. Negative pressure suction puncture may obtain more glomeruli and have lower incidence of perirenal hematoma, but have lower successful rate of renal needle biopsy.


Key words: 
Biopsy, needle; Kidney; Glomerular filtration rate; Hematoma
Psoriasis Drug Guselkumab Improved Psoriatic Arthritis Symptoms
Authors: Anita Slomski
Journal: JAMA (2020)

Guselkumab, a biologic drug approved to treat patients with moderate or severe psoriasis, significantly and safely improved psoriatic arthritis, a phase 3 trial in The Lancet concluded. Guselkumab is a human monoclonal antibody that inhibits interleukin-23.
Phase I study to assess the safety, tolerability, pharmacokinetics/pharmacodynamics and preliminary efficacy of SC10914 in patients with advanced solid tumors.
Authors: Jifang Gong, Jinhai Tang, Yongmei Yin, Dingwei Ye, Jian Zhang, Hong Zheng, Yunong Gao, Haoyuan Jang, Xiao Chen, Zhe Zhang, Lin Shen
Journal: Journal of Clinical Oncology (2020)

6047 Background: SC10914 is a highly selective inhibitor of PARP enzymes, including PARP1 and PARP2. SC10914 has a similar structure with olaparib. We conducted a phase I study to assess the safety, tolerability, PK/PD and preliminary efficacy of SC10914 in patients with advanced solid tumors. Methods: This is a phase I dose-escalation study with 3+3 design, we enrolled patients at 4 sites in China. Eligible patients were diagnosed with advanced solid malignancies who are refractory to standard therapies or for which no standard therapy exists; had measurable disease; had adequate organ function. Patients received SC10914 daily at ten escalating doses from 30 mg QD to 500 mg TID in a 28-day cycle. We obtained blood for PK and CA125 assessments. Toxic effects were assessed by CTCAE 4.03 criteria and tumour responses ascribed by RECIST 1.1 and CA125 was assessed by GCIG criteria. Results: As of January 2020, 52 patients were enrolled, of which 14 were males and 38 were females. Ten doses were escalated to 500mg TID, and no DLT was observed, and MTD was not obtained. The incidence of grade 3/4 AEs and SAEs that were related to SC10914 were 34.6% (18/52) and 13.5% (7/52). Grade 3/4 adverse reaction happened in at least two patients were anaemia/reduced hemoglobin (10/52, 19.2%), decreased WBC count (5/52, 9.6%), neutropenia (3/52, 5.8%), thrombocytopenia (2/52, 3.8%), and decreased lymphocyte count (2/52, 3.8%). A total of 17 gBRCAm evaluable ovarian cancer patients were enrolled, 6 of them had PR, the ORR was 35.3% (6/17). 10 gBRCAm ovarian cancer patients were enrolled in TID groups (including 2 patients who received BID doses at the beginning and changed to 300 mg TID dose after several cycles of treatment), 5 of them had PR, the ORR was 50% (5/10). The ORR of 400 mg TID group was 66.7%(4/6). PK data showed that the exposure of SC10914 was increased with dose increasing at the dose of 30 mg to 250 mg. The half-life of SC10914 was about 2-5 hours. Conclusions: SC10914 was safe in patients with advanced solid tumors. The main toxicity was blood-related adverse reactions. SC10914 was effective in gBRCAm ovarian cancer patients. 400 mg TID might be RP2D. Clinical trial information: NCT02940132.