Developing autonomous self-healing materials for applications in harsh conditions is challenging because the reconstruction of interaction in material for self-healing will experience significant ...resistance and fail. Herein, a universally self-healing and highly stretchable supramolecular elastomer is designed by synergistically incorporating multi-strength H-bonds and disulfide metathesis in polydimethylsiloxane polymers. The resultant elastomer exhibits high stretchability for both unnotched (14000%) and notched (1300%) samples. It achieves fast autonomous self-healing under universal conditions, including at room temperature (10 min for healing), ultralow temperature (-40 °C), underwater (93% healing efficiency), supercooled high-concentrated saltwater (30% NaCl solution at -10 °C, 89% efficiency), and strong acid/alkali environment (pH = 0 or 14, 88% or 84% efficiency). These properties are attributable to synergistic interaction of the dynamic strong and weak H-bonds and stronger disulfide bonds. A self-healing and stretchable conducting device built with the developed elastomer is demonstrated, thereby providing a direction for future e-skin applications.
Purpose Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is treatment-responsive. Definitive chemoradiation results in high cure rates but causes long-term toxicity ...and may represent overtreatment of some patients. This phase II trial evaluated whether complete clinical response (cCR) to induction chemotherapy (IC) could select patients with HPV-associated OPSCC for reduced radiation dose as a means of sparing late sequelae. Methods Patients with HPV16 and/or p16-positive, stage III-IV OPSCC received three cycles of IC with cisplatin, paclitaxel, and cetuximab. Patients with primary-site cCR to IC received intensity-modulated radiation therapy (IMRT) 54 Gy with weekly cetuximab; those with less than cCR to IC at the primary site or nodes received 69.3 Gy and cetuximab to those regions. The primary end point was 2-year progression-free survival. Results Of the 90 patients enrolled, 80 were evaluable. Their median age was 57 years (range, 35 to 73 years), with the majority having stage T1-3N0-N2b OPSCC and a history of ≤ 10 pack-years of cigarette smoking. Three cycles of IC were delivered to 77 of the 80 patients. Fifty-six patients (70%) achieved a primary-site cCR to IC and 51 patients continued to cetuximab with IMRT 54 Gy. After median follow-up of 35.4 months, 2-year progression-free survival and overall survival rates were 80% and 94%, respectively, for patients with primary-site cCR treated with 54 Gy of radiation (n = 51); 96% and 96%, respectively, for patients with < T4, < N2c, and ≤ 10 pack-year smoking history who were treated with ≤ 54 Gy of radiation (n = 27). At 12 months, significantly fewer patients treated with a radiation dose ≤ 54 Gy had difficulty swallowing solids (40% v 89%; P = .011) or had impaired nutrition (10% v 44%; P = .025). Conclusion For IC responders, reduced-dose IMRT with concurrent cetuximab is worthy of further study in favorable-risk patients with HPV-associated OPSCC. Radiation dose reduction resulted in significantly improved swallowing and nutritional status.
We previously reported durable responses and manageable safety of ibrutinib from a 3-year follow-up of treatment-naïve (TN) older patients (≥65 years of age) and relapsed/refractory (R/R) patients ...with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We now report on long-term efficacy and safety with median follow-up of 5 years in this patient population with TN (N = 31) and R/R (N = 101) CLL/SLL. With the current 5-year follow-up, ibrutinib continues to yield a high overall response rate of 89%, with complete response rates increasing over time to 29% in TN patients and 10% in R/R patients. The median progression-free survival (PFS) was not reached in TN patients. The 5-year PFS rate was 92% in TN patients and 44% in R/R patients. Median PFS in R/R patients was 51 months; in those with del(11q), del(17p), and unmutated IGHV, it was 51, 26, and 43 months, respectively, demonstrating long-term efficacy of ibrutinib in some high-risk subgroups. Survival outcomes were less robust for R/R patients with del(17p) and those who received more prior therapies. The onset of grade ≥3 cytopenias, such as neutropenia and thrombocytopenia, decreased over time. Treatment--limiting adverse events were more frequent during the first year compared with subsequent periods. These results demonstrate sustained efficacy and acceptable tolerability of ibrutinib over an extended time, providing the longest experience for Bruton tyrosine kinase inhibitor treatment in patients with CLL/SLL. These trials were registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01109069.
•Our 5-year experience shows sustained single-agent efficacy of ibrutinib in CLL patients, with complete response rates increasing over time.•Long-term ibrutinib was well tolerated with no new safety signals; rates of grade ≥3 cytopenias decreased with continued therapy.
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Ibrutinib inhibits Bruton's tyrosine kinase, a component of normal B-cell activation pathways. Ibrutinib produced responses in 71% of patients with refractory chronic lymphocytic leukemia.
Chronic ...lymphocytic leukemia (Cll) is the most common leukemia in adults. Therapy for symptomatic CLL has consisted predominantly of chemotherapeutic agents, including chlorambucil, cyclophosphamide, fludarabine, and combinations of these agents that are effective for palliation but do not improve survival.
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The addition of the anti-CD20 antibody rituximab to chemotherapy (fludarabine
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alone or in combination with cyclophosphamide
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) results in higher response rates, extended remissions, and improved overall survival.
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However, a subgroup of patients with deletion of 17p13.1 have a poor response to chemoimmunotherapy, and patients with tumors expressing unmutated immunoglobulin variable-region heavy-chain genes have shorter remissions than those with mutated . . .
Cancer stem cells (CSCs) with enhanced tumorigenicity and chemoresistance are believed to be responsible for treatment failure and tumor relapse in ovarian cancer patients. However, it is still ...unclear how CSCs survive DNA-damaging agent treatment. Here, we report an elevated expression of DNA polymerase η (Pol η) in ovarian CSCs isolated from both ovarian cancer cell lines and primary tumors, indicating that CSCs may have intrinsically enhanced translesion DNA synthesis (TLS). Down-regulation of Pol η blocked cisplatin-induced CSC enrichment both in vitro and in vivo through the enhancement of cisplatin-induced apoptosis in CSCs, indicating that Pol η-mediated TLS contributes to the survival of CSCs upon cisplatin treatment. Furthermore, our data demonstrated a depletion of miR-93 in ovarian CSCs. Enforced expression of miR-93 in ovarian CSCs reduced Pol η expression and increased their sensitivity to cisplatin. Taken together, our data suggest that ovarian CSCs have intrinsically enhanced Pol η-mediated TLS, allowing CSCs to survive cisplatin treatment, leading to tumor relapse. Targeting Pol η, probably through enhancement of miR-93 expression, might be exploited as a strategy to increase the efficacy of cisplatin treatment.
Summary Background Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, ...its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia. Methods In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov , number NCT01105247. Findings Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65–84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1–2). 21 (68%) patients had diarrhoea (grade 1 in 14 45% patients, grade 2 in three 10% patients, and grade 3 in four 13% patients). 15 (48%) patients developed nausea (grade 1 in 12 39% patients and grade 2 in three 10% patients). Ten (32%) patients developed fatigue (grade 1 in five 16% patients, grade 2 in four 13% patients, and grade 3 in one 3% patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22·1 months (IQR 18·4–23·2), 22 (71%) of 31 patients achieved an objective response (95% CI 52·0–85·8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response. Interpretation The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase 3 trials. Funding Pharmacyclics, Leukemia and Lymphoma Society, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158 to Prof J C Byrd MD.
In this paper, a dynamics model of the gear-bearing transmission system with bending and torsion coupling is established, and the influence of gear shifted on the vibration characteristics of the ...gear system is considered. First, the time-varying mesh stiffness of the profile shifted gear is derived by using the potential energy method. Then, based on the Lagrange equation numerical method, the vibration differential equation of the model is obtained, and the differential equation is solved by the fourth-order Runge-Kutta method. Finally, the influence of the profile shifted coefficient and input torque on the vibration characteristics of the gear transmission system is analyzed by using the time domain graph and the frequency domain graph. The conclusions drawn from this study can help engineers better understand the running performance and vibration characteristics of profile shifted gear.
Kaplan turbines are widely utilized in low-head and large flow power stations. This paper employs Computational Fluid Dynamics (CFD) to complete numerical calculations of the full flow channel under ...different blade angles and various guide vane openings, based on 25 off-cam experimental working conditions. The internal flow characteristics of the runner blade and draft tube are analyzed, and a discriminant number for quantitatively assessing the flow uniformity of the draft tube is proposed. The results indicate that low-frequency and high-amplitude pressure pulsations occur on the high- and low-pressure edge of the blade when the opening is small, with pulsations decreasing as the opening increases. The inner flow line of the draft tube is disturbed when both the blade angle and opening are small. Additionally, the secondary frequency of the draft tube inlet is double that of the vane passing frequency. The discriminant number of the flow inhomogeneity approaches 0 under optimal flow conditions. The number increases continuously with the decrease in efficiency, and the flow in the three piers of draft tube becomes more nonuniform. The research results provide a reference for enhancing performance and ensuring the operational stability of Kaplan turbines.
Light-emitting diode (LED) standard lamps are interesting since the traditional incandescent standard lamps for photometry are difficult to obtain. Many of the National Metrology Institutes have ...started projects to study the use of LED standards for photometric comparison. The National Institute of Metrology, China, has developed a type of LED filament lamp for total luminous flux. The lamp mimics the 4π incandescent standard lamp and has no space for an active temperature control component. A temperature dependence correction method is reported using the coefficient of the lamp voltage to the output luminous flux. The luminous flux correction is derived from the lamp voltage value. By applying correction, the stability test of the LED filament lamp shows that the ageing effect was estimated to be less than 0.1%/210 days. The temperature dependence was suppressed to less than 0.1% for a range of 21 °C ± 2 °C, which could be due to possible temperature fluctuations of the lamp ambient temperature during measurement by the goniophotometer or integrating sphere.
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