To determine whether changes in objective response measures proposed by the National Institutes of Health correlate with clinical benefit, such as symptom burden, quality of life, and survival ...outcomes, we analyzed data from a multicenter prospective cohort of 283 patients with chronic graft-versus-host disease requiring systemic treatment. The median follow-up time of survivors was 25.1 months (range, 5.4-47.7 months) after enrollment. Symptom measures included the Lee symptom scale and 10-point patient-reported symptoms. Quality-of-life measures included the Short Form-36, Functional Assessment of Cancer Therapy–Bone Marrow Transplantation, and Human Activities Profile. Overall and organ-specific responses were calculated by comparing manifestations at the 6-month visit and those at the enrollment visit using a provisional algorithm. Complete or partial responses were considered “response,” and stable or progressive disease was considered “no response.” Overall response rate at 6 months was 32%. Organ-specific response rates were 45% for skin, 23% for eyes, 32% for mouth, and 51% for gastrointestinal tract. Response at 6 months, as calculated according to the provisional response algorithm, was correlated with changes in symptom burden in patients with newly diagnosed chronic graft-versus-host disease, but not with changes in quality of life or survival outcomes. Modification of the algorithm or validation of other more meaningful clinical endpoints is warranted for future clinical trials of treatment for chronic graft-versus-host disease.
Rapeseed cleaning loss is an important factor to weigh rapeseed combine harvester performance. With the development of sensor technology, establishing a rapeseed cleaning loss monitoring system can ...be interesting and necessary. However, the rapeseed combine harvester made in China is always with larger vibration, which is not beneficial for sensor monitoring accuracy. Experiment results indicate that inertia force from vibrating sieve unbalanced motion has the greatest influence on the monitoring accuracy of the sensor in its installation position. To reduce the effect of vibration on monitoring accuracy of the sensor, the vibration absorption and isolation structure for cleaning loss sensor has been designed. Moreover, the vibration isolation design was performed on the basis of vibration suppression. The vibration isolation rubber was designed to isolate the vibration at the joint of the sensor with the frame. The experimental results shown that the above design can reduce the vibration disturbance and highlight the grain collision signal greatly, which is beneficial for improving the sensor discrimination ability.
Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring >100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of ...this analysis is to describe the onset, course, morbidity, and mortality of and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n = 909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, 128-204) days after HCT. Although 51 out of 83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure-free survival was only 7.1 months (95% confidence interval, 3.4-19.1 months), and estimated overall survival (OS) at 2 years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n = 55) and controls (n = 50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG; an epidermal growth factor EGF receptor ligand) was elevated, and an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD.
•Under current treatment approaches, patients with LA GVHD have poor overall and failure-free survival.•Levels of AREG are elevated in LA GVHD, and the AREG/EGF ratio is predictive of overall survival and nonrelapse mortality in LA GVHD.
To improve the driving comfort of combine harvesters, driver seat low-frequency vibration and related driver ride-comfort problems were investigated on a Chinese CFFL-850 crawler-type full-feed ...combine harvester based on ISO2631. Driver vibration and driving seat transmission characteristics were measured under the following conditions: no-load idling, driving on the road, driving in the field, and simulated harvesting. The root mean square values composite vibration under four conditions were 3.63 m/s2, 2.35 m/s2, 3.34 m/s2, and 2.67 m/s2, respectively. For the same condition, the maximum root mean square scores of vibration component on driver whole-body occurred in the seat support surface (test point 1) and vertical direction (Z direction), which were 3.56 m/s2, 2.05 m/s2, 3.15 m/s2, and 2.43 m/s2, respectively. The test point 2 to test point 1 vertical-transfer function curve trends were nearly identical. Nearly all of the transfer coefficients were greater than 1 in the range of 1-50 Hz, therefore, the seat vibration attenuation performance was poor. Based on the analysis results, the driver seat structure was altered and a verification test was performed. The test results indicated that after an X-damping mechanism was installed, vibration acceleration, on the surface of the seat support under the road-driving conditions, decreased from 2.35 m/s2 to 1.68 m/s2. Under the simulated harvesting condition, the vibration acceleration decreased from 2.56 m/s2 to 1.46 m/s2. Nearly all of the seat vertical transfer coefficients were less than 1 within the frequency range of 1-80 Hz, therefore the dynamic comfort of the seat was ameliorated after structural improvement.
Neoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with ...antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC.
We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m2 IV weekly ×12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor ER and grade).
Seventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER+ disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue.
Neoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR; however, 47% were responders using pCR and/or CPS + EG score ≤2. ER positive patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for patients with ER positive LABC.
Pathologic complete response (pCR) after neoadjuvant chemotherapy is associated with improved survival in locally advanced and inflammatory breast cancer. Neoadjuvant sunitinib + paclitaxel followed by doxorubicin + cyclophosphamide with G-CSF therapy resulted in a 27% pCR rate in this single-arm, phase II trial. ER+ patients had higher response rates (64%) using the CPS + EG score and pCR, suggesting promising incremental benefit.
ML-driven software is heralded as the next majoradvancement in software engineering; existing software todaycan benefit from being evolved to be ML-driven. In this paper, we contribute practical ...knowledge about evolving software tobe ML-driven, utilizing real-world A/B testing. We draw onexperiences evolving two software features from the Windowsoperating system to be ML-driven, with more than ten real-world A/B tests on millions of PCs over more than two years.We discuss practical reasons for using A/B testing to engineerML-driven software, insights for success, as well as on-going real-world challenges. This knowledge may help practitioners, as wellas help direct future research and innovations.
DNA amplification, particularly of chromosomes 8 and 11, occurs frequently in breast cancer and is a key factor in tumorigenesis, often associated with poor prognosis. The mechanisms involved in the ...amplification of these regions are not fully understood. Studies from model systems have demonstrated that palindrome formation can be an early step in DNA amplification, most notably seen in the breakage-fusion-bridge (BFB) cycle. Therefore, palindromes might be associated with gene amplicons in breast cancer. To address this possibility, we coupled high-resolution palindrome profiling by the Genome-wide Analysis of Palindrome Formation (GAPF) assay with genome-wide copy-number analyses on a set of breast cancer cell lines and primary tumors to spatially associate palindromes and copy-number gains. We identified GAPF-positive regions distributed nonrandomly throughout cell line and tumor genomes, often in clusters, and associated with copy-number gains. Commonly amplified regions in breast cancer, chromosomes 8q and 11q, had GAPF-positive regions flanking and throughout the copy-number gains. We also identified amplification-associated GAPF-positive regions at similar locations in subsets of breast cancers with similar characteristics (e.g., ERBB2 amplification). These shared positive regions offer the potential to evaluate the utility of palindromes as prognostic markers, particularly in premalignant breast lesions. Our results implicate palindrome formation in the amplification of regions with key roles in breast tumorigenesis, particularly in subsets of breast cancers.
To evaluate the treatment, outcome, and prognostic factors in patients with head and neck sarcomas treated in an academic medical center.
Case series.
Academic medical center.
We performed a ...retrospective analysis of adult patients (n = 97) with primary head and neck sarcomas treated between 2000 and 2012. We analyzed the treatment, outcome, and potential factors predictive of disease-free survival and disease-specific survival. We also evaluated the outcome and prognostic factors in patients with bone and soft tissue sarcomas.
The median overall survival was 6.8 years, with 2-year and 5-year overall survival rates of 78% (95% confidence interval CI, 66%-86%) and 59% (95% CI, 44%-72%), respectively. Univariable analysis revealed that age at diagnosis (>60 years: hazard ratio HR, 2.7; 95% CI, 1.2-6.2; P = .01), surgical intervention (HR, 8.3; 95% CI, 3.5-19.5; P < .001), and metastatic disease (HR, 4.3; 95% CI, 1.3-13.6; P = .01) were significantly associated with disease-specific survival.
In this study, patients over the age of 60 years at diagnosis and those with inoperable disease at initial presentation had significantly worse disease-specific survival. Surgical intervention remains the optimal treatment modality for those with resectable disease and was associated with significantly better survival in this heterogeneous series. Further multi-institutional studies are required to better define prognostic factors in individual histological subtypes.
Platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-beta1 (TGF-beta1) are critically involved in idiopathic pulmonary fibrosis by inducing the proliferation and ...transdifferentiation of lung fibroblasts. In the present study, we examined the impact of diallyl disulfide (DADS), a garlic-derived compound, on such pathological conditions. DADS showed profound inhibitory effects on the PDGF-BB-induced proliferation of human and mouse lung fibroblasts. DADS also abrogated the TGF-beta1-induced expression of alpha-smooth muscle actin, type I collagen and fibronectin. Following treatment with DADS, the expression of cyclooxygenase-2 (COX-2) and the synthesis of prostaglandin E^sub 2^ (PGE^sub 2^) were found to be markedly enhanced, which in turn led to elevated cAMP levels in lung fibroblasts. Notably, the effect of DADS was largely abolished in the presence of either COX inhibitor indomethacin or siRNA-targeting COX-2, or in the absence of the PGE^sub 2^ receptor EP2, supporting an essential role for the COX-2-PGE^sub 2^-cAMP autocrine loop. Furthermore, we demonstrated that the upregulated expression of COX-2 was a result of increased level of histone 3 acetylation at COX-2 locus in DADS-treated cells. Together, these results suggest that DADS, by inducing COX-2 expression, may have therapeutic potential in treating lung fibrosis.PUBLICATION ABSTRACT
Platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-β1 (TGF-β1) are critically involved in idiopathic pulmonary fibrosis by inducing the proliferation and transdifferentiation ...of lung fibroblasts. In the present study, we examined the impact of diallyl disulfide (DADS), a garlic-derived compound, on such pathological conditions. DADS showed profound inhibitory effects on the PDGF-BB-induced proliferation of human and mouse lung fibroblasts. DADS also abrogated the TGF-β1-induced expression of α-smooth muscle actin, type I collagen and fibronectin. Following treatment with DADS, the expression of cyclooxygenase-2 (COX-2) and the synthesis of prostaglandin E.sub.2 (PGE.sub.2) were found to be markedly enhanced, which in turn led to elevated cAMP levels in lung fibroblasts. Notably, the effect of DADS was largely abolished in the presence of either COX inhibitor indomethacin or siRNA-targeting COX-2, or in the absence of the PGE.sub.2 receptor EP2, supporting an essential role for the COX-2-PGE.sub.2-cAMP autocrine loop. Furthermore, we demonstrated that the upregulated expression of COX-2 was a result of increased level of histone 3 acetylation at COX-2 locus in DADS-treated cells. Together, these results suggest that DADS, by inducing COX-2 expression, may have therapeutic potential in treating lung fibrosis. Keywords Diallyl disulfide * Cyclooxygenase * PGE2 * Fibrosis * Histone acetylation
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