Dose-escalated radiation therapy for localized prostate cancer (PCa) has a clear therapeutic benefit; however, escalated doses may also increase injury to noncancerous tissues. Radiosensitizing agents can improve ionizing radiation (IR) potency, but without targeted delivery, these agents will also sensitize surrounding normal tissues. Here we describe the development of prostate-targeted RNAi agents that selectively sensitized prostate-specific membrane antigen-positive (PSMA-positive) cells to IR. siRNA library screens identified DNA-activated protein kinase, catalytic polypeptide (DNAPK) as an ideal radiosensitization target. DNAPK shRNAs, delivered by PSMA-targeting RNA aptamers, selectively reduced DNAPK in PCa cells, xenografts, and human prostate tissues. Aptamer-targeted DNAPK shRNAs, combined with IR, dramatically and specifically enhanced PSMA-positive tumor response to IR. These findings support aptamer-shRNA chimeras as selective sensitizing agents for the improved treatment of high-risk localized PCa.

Activation of the p53 pathway has been considered a therapeutic strategy to target cancers. We have previously identified several p53-activating small molecules in a cell-based screen. Two of the compounds activated p53 by causing DNA damage, but this modality was absent in the other four. We recently showed that one of these, BMH-21, inhibits RNA polymerase I (Pol I) transcription, causes the degradation of Pol I catalytic subunit RPA194, and has potent anticancer activity. We show here that three remaining compounds in this screen, BMH-9, BMH-22, and BMH-23, cause reorganization of nucleolar marker proteins consistent with segregation of the nucleolus, a hallmark of Pol I transcription stress. Further, the compounds destabilize RPA194 in a proteasome-dependent manner and inhibit nascent rRNA synthesis and expression of the 45S rRNA precursor. BMH-9-and BMH-22-mediated nucleolar stress was detected in ex vivo-cultured human prostate tissues indicating good tissue bioactivity. Testing of closely related analogues showed that their activities were chemically constrained. Viability screen for BMH-9, BMH-22, and BMH-23 in the NCI60 cancer cell lines showed potent anticancer activity across many tumor types. Finally, we show that the Pol I transcription stress by BMH-9, BMH-22, and BMH-23 is independent of p53 function. These results highlight the dominant impact of Pol I transcription stress on p53 pathway activation and bring forward chemically novel lead molecules for Pol I inhibition, and, potentially, cancer targeting. Mol Cancer Ther; 13(11); 2537-46. Ó2014 AACR.

Oxidative stress induced by hyperglycemia or chronic inflammation can limit diabetic wound healing, resulting in diabetic foot ulcers. Hydrogen has the potential to act as an antioxidant and scavenge reactive oxygen species, thereby attenuating inflammation in these chronic wounds. However, most of the reported H 2 delivery systems for wound healing, including hydrogen gas, hydrogen-rich water, and hydrogen-rich saline, are very short-lived for the low solubility of hydrogen gas.Here, we introduce a hydrogen-producing hydrogel made of living Chlorella and bacteria within a cell-impermeable casing that can continuously produce hydrogen for 60 h. This microbe−hydrogel system can selectively reduce highly toxic •OH and ONOO − species and reduce inflammation. Additional experiments indicated that the microbe−hydrogel dressing could promote cell proliferation and diabetic wound healing by almost 50% at day 3. The symbiotic algae−bacteria hydrogel has excellent biocompatibility and reactive oxygen species scavenging features, indicating it has great promise for clinical use.

DNA damage response (DDR) pathways have been extensively studied in cancer cell lines and mouse models, but little is known about how DNA damage is recognized by different cell types in nonmalignant, slowly replicating human tissues. Here, we assess, using ex vivo cultures of human prostate tissue, DDR caused by cytotoxic drugs (camptothecin, doxorubicin, etoposide, and cisplatin) and ionizing radiation (IR) in the context of normal tissue architecture. Using specific markers for basal and luminal epithelial cells, we determine and quantify cell compartment-specific damage recognition. IR, doxorubicin, and etoposide induced the phosphorylation of H2A.X on Ser 139 (γH2AX) and DNA damage foci formation. Surprisingly, luminal epithelial cells lack the prominent γH2AX response after IR when compared with basal cells, although ATM phosphorylation on Ser 1981 and 53BP1 foci were clearly detectable in both cell types. The attenuated γH2AX response seems to result from low levels of total H2A.X in the luminal cells. Marked increase in p53, a downstream target of the activated ATM pathway, was detected only in response to camptothecin and doxorubicin. These findings emphasize the diversity of pathways activated by DNA damage in slowly replicating tissues and reveal an unexpected deviation in the prostate luminal compartment that may be relevant in prostate tumorigenesis. Detailed mapping of tissue and cell type differences in DDR will provide an outlook of relevant responses to therapeutic strategies. Cancer Res; 70(21); 8630-41. ©2010 AACR.

Among different kinds of photoactuators available, those based on liquid‐crystal polymer networks (LCNs) are gathering a great deal of attention due to their fast response and versatility of structural design. However, only a few reports have focused on the phototriggered LCN actuators for complex actuation and multifunction properties. Here, a phototriggered LCN‐based photonic actuator with quasi‐bilayer structure that exhibits fast and reversible shape changes is created by infiltrating a LCN precursor–graphene oxide mixture into a silica opal template, ultraviolet photopolymerization, and removing the template. Particularly, the phototriggered selective actuation behavior is achieved in dual‐phase LCN‐based photonic actuators with macroscopically alternating nematic (N) and isotropic (I) phase, which enables versatile actuation modes and allows multiple shape changes. In addition, a two‐segmented, dual‐phase LCN‐based photonic actuator exhibits self‐oscillating motion when a responsive N‐phase region as localized active point is irradiated, which arises from the self‐shadowing of the passive I‐phase region. To demonstrate the potential application of this self‐oscillating motion behavior, a photoelectric energy conversion device that is capable of converting light energy to electric energy is constructed.

ObjectiveTo assess the efficacy and safety of transarterial Chemoembolization (TACE) combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma (HCC).Patients and MethodsThe data of patients with unresectable HCC administered a combination therapy with TACE and lenvatinib plus sintilimab were retrospectively assessed. Patients received lenvatinib orally once daily 2 weeks before TACE, followed by sintilimab administration at 200 mg intravenously on day 1 of a 21-day therapeutic cycle after TACE. The primary endpoints were objective response rate (ORR) and duration of response (DOR) by the modified RECIST criteria.ResultsMedian duration of follow-up was 12.5 months (95%CI 9.1 to 14.8 months). ORR was 46.7% (28/60). Median DOR in confirmed responders was 10.0 months (95%CI 9.0-11.0 months). Median progression-free survival (PFS) was 13.3 months (95%CI 11.9-14.7 months). Median overall survival (OS) was 23.6 months (95%CI 22.2-25.0 months).ConclusionsTACE combined with lenvatinib plus sintilimab is a promising therapeutic regimen in unresectable hepatocellular carcinoma.

Acquisition of laser frequency with high resolution under continuous and abrupt tuning conditions is important for sensing, spectroscopy and communications. Here, a single microresonator provides rapid and broad-band measurement of frequencies across the optical C-band with a relative frequency precision comparable to conventional dual frequency comb systems. Dual-locked counter-propagating solitons having slightly different repetition rates are used to implement a Vernier spectrometer. Laser tuning rates as high as 10 THz/s, broadly step-tuned lasers, multiline laser spectra and also molecular absorption lines are characterized using the device. Besides providing a considerable technical simplification through the dual-locked solitons and enhanced capability for measurement of arbitrarily tuned sources, this work reveals possibilities for chipscale spectrometers that greatly exceed the performance of table-top grating and interferometerbased devices.Frequency-agile lasers are ubiquitous in sensing, spectroscopy and optical communications 1-3 and measurement of their optical frequency for tuning and control is traditionally performed by grating and interferometerbased spectrometers, but more recently these measurements can make use of optical frequency combs 4-6 . Frequency combs provide a remarkably stable measurement grid against which optical signal frequencies can be determined subject to the ambiguity introduced by their equally spaced comb lines. The ambiguity can be resolved for continuously frequency swept signals by counting comb teeth 7 relative to a known comb tooth; and this method has enabled measurement of remarkably high chirp rates 8 . However, signal sources can operate with abrupt frequency jumps so as to quickly access a new spectral region or for switching purposes, and this requires a different approach. In this case, a second frequency comb with a different comb line spacing can provide a Vernier scale 9 for comparison with the first comb to resolve the ambiguity under quite general tuning conditions 9-11 . This Vernier concept is also used in dual comb spectroscopy 12,13 , but in measuring active signals the method can be significantly enhanced to quickly identify signal frequencies through a signal correlation technique 9 . The power of the Vernier-based method relies upon mapping of optical comb frequencies into a radio-frequency grid of frequencies, the precision of which is set by the relative line-by-line frequency stability of the two frequency combs. This stability can be guaranteed by self-referencing each comb using a common high-stability radio-frequency source or through optical locking of each comb to reference lasers whose relative stability is ensured by mutual locking to a common optical cavity.Here, a broad-band, high-resolution Vernier soliton microcomb spectrometer is demonstrated using a single miniature comb device that generates two mutuallyphase-locked combs. The principle of operation relies upon an optical phase locking effect observed in the generation of counter-pr...

Hydrophobic membranes used in membrane distillation (MD) systems are often subject to wetting during long-term operation. Thus, it is of great importance to fully understand factors that influence the wettability of hydrophobic membranes and their impact on the overall separation efficiency that can be achieved in MD systems. This Critical Review summarizes both fundamental and applied aspects of membrane wetting with particular emphasis on interfacial interaction between the membrane and solutes in the feed solution. First, the theoretical background of surface wetting, including the relationship between wettability and interfacial interaction, definition and measurement of contact angle, surface tension, surface free energy, adhesion force, and liquid entry pressure, is described. Second, the nature of wettability, membrane wetting mechanisms, influence of membrane properties, feed characteristics and operating conditions on membrane wetting, and evolution of membrane wetting are reviewed in the context of an MD process. Third, specific membrane features that increase resistance to wetting (e.g., superhydrophobic, omniphobic, and Janus membranes) are discussed briefly followed by the comparison of various cleaning approaches to restore membrane hydrophobicity. Finally, challenges with the prevention of membrane wetting are summarized, and future work is proposed to improve the use of MD technology in a variety of applications.