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The liquid–vapor phase distribution and displacement in the capillary evaporator of a loop heat pipe (LHP) are key phenomena affecting the steady-state and transient operating behavior. This study conducts optical observation of liquid–vapor phase behavior in the evaporator using a transparent glass tube heated by far-infrared radiation during start-up of the LHP. A quartz wick-acetone LHP system is designed, fabricated, and operated successfully with a heat flux of 1 W/cm 2 transported by the cylindrical evaporator. To investigate effect of the liquid–vapor phase distribution in the evaporator at the initial state, start-up experiments with eight phase patterns—which are either liquid-saturated or two-phase in each of the inlet of the vapor line, grooves, and compensation chamber (CC)—are performed. The phase distribution affects the temperature profile although it has no effect upon the steady-state characteristics, and nucleate boiling occurs in the wick or groove simultaneously with evaporator-temperature drop when both the grooves and the inlet of the vapor line are completely filled with liquid. Liquid–vapor displacements from start-up to the steady-state are classified into four transient behaviors, which include boiling in the CC and meniscus oscillation at the three phase contact line within the case, wick, and groove. [ABSTRACT FROM AUTHOR]

Healthy bone is commonly irradiated during radiotherapy for many cancers, and bone fractures can be a late complication. A recent study revealed a higher incidence of rib fractures after breast irradiation with protons (7%) compared to photons (1%) at the same dose, but the underlying biological mechanisms are unknown. Here we used in vitro experiments, supported by Monte Carlo track structure simulations, to investigate differences in bone cell responses to proton and photon radiation, and to identify potential therapeutic interventions. We used TOPAS-nBio, a radiobiology simulation toolkit, to simulate a segment of bone using geometric models of bone cells (osteoblasts, osteoclasts, and osteocytes). Photon and proton tracks were simulated through bone matrix to investigate energy distributions received by each cell. For in vitro experiments, we utilized the murine osteocytic cell line Ocy454. Cells were irradiated with different doses of protons or photons. Surviving fraction as a function of dose was determined using colony formation assays. DNA double-strand breaks were assessed by 53BP1 foci assay. For PTH treatments, cells were treated with 10 nM human PTH(1-34) for 24 hours prior to irradiation. All experiments were repeated independently three or more times. Statistical analysis was performed by unpaired t-test with Bonferroni correction. Monte Carlo track simulations showed osteocytes are the bone cell most likely to receive radiation damage, particularly with protons. In the case of large multi-nucleated osteoclasts, both photons and protons spared some of the nuclei, suggesting functional sparing of osteoclasts from radiation damage. We therefore focused our in vitro experiments on Ocy454 osteocytes. Interestingly, the surviving fraction of osteocytes was significantly lower after protons compared to photons for all investigated doses of 1 to 8 Gy. The dose for 10% surviving fraction was 5.38 Gy for protons and 7.46 Gy for photons (Relative Biological Effect 1.39). Although protons and photons induced similar numbers of 53BP1 foci at 1 hour (79% vs. 72% cells with foci), a significantly higher number of foci was observed at 24 hours after protons compared to photons (22% vs. 6.5%, p=0.0078), suggestive of persistent DNA damage after protons. Remarkably, we found that pre-treatment with parathyroid hormone (PTH) decreased 53BP1 foci at 24 hours in proton-irradiated cells to levels comparable to that of non-irradiated cells (22% without PTH vs. 6.3% with PTH, p=0.014). Surviving fraction of osteocytes was lower after proton compared to photon irradiation, suggesting a greater sensitivity of osteocytes to protons. Protons result in greater DNA damage in osteocytes, but this damage may be mitigated with the addition of PTH. Further study is needed to investigate the potential of PTH to reduce bone damage induced by proton irradiation. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Radiotherapy (RT) with or without androgen deprivation therapy (ADT) plays a key role in the salvage treatment of prostate cancer recurrent after prostatectomy. However, not all patients benefit from salvage therapy, and there is an unmet need for biomarkers to distinguish responders from non-responders. Prostate cancer depends on androgen receptor (AR) signaling, and expression of AR splice variants (ARVs) that enable androgen-independent AR signaling is associated with resistance to ADT in the metastatic setting. Recent in vitro data suggest that ARVs also mediate DNA repair after irradiation, suggesting that ARV expression may also be a biomarker of resistance to RT. However, the landscape of ARV expression in primary prostate cancer and its effect on treatment outcomes remain unexplored. Here, we hypothesized that ARVs may be detectable in primary prostate cancer and furthermore may modulate response to salvage RT+ADT.Materials/methods: We retrospectively identified 46 prostate cancer patients treated with prostatectomy followed by salvage RT+ ADT at a single institution from 1995 to 2012. Median age at salvage was 64.5 years. The indication for salvage therapy was biochemical failure after an undetectable post-operative PSA in 72%, gross local recurrence in 17%, and persistently elevated PSA after surgery in 11%. Median RT dose was 64.8 Gy, and all patients received concurrent ADT. We comprehensively interrogated the landscape of ARVs by performing ultra-deep targeted RNA-seq of archival formalin-fixed paraffin-embedded prostatectomy samples. Using a custom library of > 3000 primers spanning all AR exons and introns, we evaluated 21 native splice junction sites and 20 splice variants with a mean depth of coverage of > 5000x. We tested for association between splice variant expression and clinical outcomes using the log-rank test and Cox proportional hazards model.Results: In total, 76% of patients had one or more detectable AR splice variants. The most commonly detected variants were AR-45 (exon 1b-2) in 41%, AR-V9 (exon 3-cryptic exon (CE) 5) in 20%, and AR-V7 (exon 3-CE3) in 13%. At a median follow-up of 33.8 months, biochemical progression-free survival (BPFS) at 3 years was 60%, distant metastasis-free survival was 90%, and overall survival was 100%. Among detected splice variants, only AR-V7 was associated with differential clinical outcomes, with a median BPFS of 10.9 months in AR-V7 positive vs 73.4 months in AR-V7 negative patients (P = 0.0020, HR 5.23, 95% CI 1.62-16.87).Conclusion: Using a custom ultra-deep targeted RNA-Seq approach, we provide among the first comprehensive descriptions of the AR splice variant landscape in primary prostate cancer. Moreover, we show that detectable AR-V7 expression in prostatectomy specimens was associated with inferior outcomes following subsequent salvage RT+ADT, suggesting for the first time that AR-V7 may modulate outcomes for localized as well as metastatic disease. [ABSTRACT FROM AUTHOR]

Trimodality therapy (TMT), which consists of transurethral resection of bladder tumor (TURBT) followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood. We characterized the genomic and transcriptomic landscape associated with response to TMT through whole exome sequencing (WES) and expression profiling. MIBC patients treated with TMT at a single institution were identified. DNA and RNA were extracted from available FFPE pre-treatment TURBT samples, and WES and transcriptome-wide expression profiling were performed. WES data were analyzed by standard mutation analysis pipelines with a common variant filter to account for lack of matched germline samples. Somatic mutations, insertion/deletions, and copy number variations were identified. Molecular subtypes and DNA damage response (DDR) pathway scores were derived from expression profiles. Responders (R) were defined as patients with complete response at post-treatment cystoscopy and no recurrence. Nonresponders (NR) were defined as patients with incomplete response at post-treatment cystoscopy, those who underwent salvage cystectomy, or those with regional/distant disease progression. Pre-treatment TURBT FFPE samples from 77 selected TMT patients were successfully sequenced and passed quality control metrics, 68 of which had matched transcriptomic profiling. The median age of the cohort was 72.7 years; 23% were female. All patients had MIBC (87% T2, 13% T3/T4) and the majority were treated with concurrent cisplatin-based chemotherapy. Median follow-up was 42 months in alive patients. Thirty-nine patients were classified as NR, while 38 were R. Mean somatic tumor mutational burden among R and NR was 13.5 (range, 4.2-31.5) and 11.3 (range, 3.4-26.8) mutations/megabase, respectively (p=0.08). Exploratory analyses of DDR pathways revealed more patients classified as R had mutations in ERCC2 (n=7) as compared to NR (n=1), p=0.023. Six of these 8 patients with ERCC2 mutations received cisplatin-based chemotherapy; of the 2 that did not, 1 was NR. Samples with ERCC2 mutations had higher hallmark DNA repair scores (median 0.110 versus -0.310, p=0.02), suggesting dysregulation of DDR. ERCC2 mutant tumors were also enriched for GSC luminal subtype compared to ERCC2 wildtype (83% vs. 37% luminal; p=0.03). Patients with ERCC2 mutations had improved disease-specific survival (HR 0.17 (95%CI: 0.064-0.41), p=0.04). Consistent with these results, in vitro studies showed ERCC2 mutant bladder cancer cell lines are significantly more sensitive to cisplatin and radiation than isogenic ERCC2 wildtype cells. Our data demonstrate that alterations in ERCC2, a crucial DDR gene, may be associated with improved response to TMT. These findings require validation in larger cohorts. [ABSTRACT FROM AUTHOR]

Purpose Magnitude of functional recovery of the left ventricle (LV) is one of the critical determinants of prognosis post-implantation of ventricular assist device (iVAD) for non-ischemic dilated cardiomyopathy (NIDCM). Although predictive factors of the functional recovery are not fully understood, presence of immunocompetent cells in the myocardium is reported to be associated with the pathological stage and/or the myocardial viability. We aimed to explore relationships between functional recovery post-iVAD implantation and distribution of the immunocompetent cells in NIDCM. Methods In the last 5 years, iVAD such as HeartMateII was implanted in 50 patients with NIDCM for bridge-to-transplantation purpose, followed by β blocker and/or ACE inhibitor in the aim to enhance functional recovery. Results During the iVAD support, 12 patients (24%) underwent heart transplantation, while 2 patients (4%) died due to cerebral infarction. Four patients (8%) were treated for congestive heart failure in-hospital, while freedom from heart failure was 96±0.0% at 1 year and 89±0.1% at 5 years. Echocardiographical dimension of the LV was a significant predictive factor of heart failure post-iVAD implantation (P <0.05). There were 4 cases (8%) who showed improvement of EF by 10% or more at 6 months post-iVAD implantation. These 4 patients did not show death or heart failure during the iVAD support. While there was no significant predictive factor of improvement of EF by 10% or more, immunocompetent cells, such as T cells or macrophage, were predominantly present in the LV myocardium of the 4 patients showing the functional recovery post-iVAD implantation, as compared to that of the other patients (Figure). Conclusion Despite aggressive medical treatments post-iVAD implantation, functional recovery was not frequently seen in advanced stage of NIDCM. Immunocompetent cells in the LV myocardium might be a key to predict myocardial viability of this pathology. [ABSTRACT FROM AUTHOR]