Deep PSA response and extended time-to-nadir as robust predictors of survival in Asian patients with de novo metastatic hormone-sensitive prostate cancer receiving upfront intensified treatment.

INTRODUCTION: In de novo metastatic hormone-sensitive prostate cancer (mHSPC) treated with upfront intensification using androgen receptor signaling inhibitor or chemotherapy (Docetaxel), achieving a PSA nadir less than 0.2 ng/mL, indicative of superior survival in trials, may often be unattainable in real-world settings. We explored the predictive value of the degree of PSA decline and time to PSA nadir (TTPN) on oncological outcomes. METHODS: A prospectively maintained database of consecutive prostate cancer cases in Hong Kong was accessed. Patients diagnosed with de novo mHSPC from 2016 to 2022 and treated with upfront intensification were included in this analysis. Landmark analysis on PSA kinetics at 6-months following treatment intensification was performed. They were classified based on 1) TTPN (≥6 months vs. <6 months), and 2) a combined response (deep responders achieving both ≥95% PSA decline and TTPN ≥ 6 months vs. shallow responders). Multivariable regression analysis was employed to identify the effects of confounders. FINDINGS: A total of 131 patients were included in this analysis. Classifying patients by combined response best predicted survival outcomes. Deep responders had better progression-free survival (HR = 0.56; 95%CI = 0.34-0.91; p = 0.019), overall survival (HR = 0.50; 95%CI = 0.26-0.97; p = 0.036), and cancer-specific survival (HR = 0.43; 95%CI = 0.19-0.99; p = 0.042). Difference in overall survival remained significant after adjustment in multivariable regression analysis. CONCLUSION: Our analysis demonstrates that alternative PSA targets can predict treatment response and survival outcomes in de novo mHSPC patients in a real-world setting, providing valuable information for patient counselling and potentially guiding future trial design.

Prior disclosure and emotional expression: Interactive effects on post-traumatic stress disorder symptoms.

Background Previous research has revealed mixed findings with regard to the effects of disclosure on trauma recovery. More recently, studies on psychological trauma have found associations among religion, meaning, and health. This study investigated prior disclosure as a moderator for the association between religious emotional expression and adaptive trauma processing, as measured by post-traumatic stress disorder (PTSD) symptoms. Methods Using Pennebaker's written emotional expression paradigm, 105 participants were assigned to either a conventional trauma-writing condition or religious trauma-writing condition. PTSD symptoms were assessed at baseline and again at one-month post writing. Results A two-way interaction was found between prior disclosure and writing condition on PTSD symptoms at follow-up. For the religious trauma-writing condition only, there was a significant difference between low versus high disclosure participants in PTSD symptoms at follow-up, such that low prior disclosure participants registered fewer PTSD symptoms than high prior disclosure participants, while prior disclosure did not have such effect in the conventional trauma-writing condition. LIMITATIONS: This two-way interaction may be further qualified by other important psychosocial variables, such as differences in personality, coping style, social support, or use of prayer as a form of disclosure, which were not assessed in this study. Conclusion Religious emotional expression may encourage adaptive trauma processing, especially for individuals with low prior disclosure. These findings encourage further investigation of the conditions under which disclosure and religion may be a beneficial factor in trauma adaptation and treatment.

Emotional intelligence, trauma severity, and emotional expression.

This study investigated Emotional Intelligence (EI) as a moderator for the association between emotional expression and adaptive trauma processing, as measured by depressive symptoms. Using Pennebaker's written emotional expression paradigm, 105 participants were assigned to either a conventional trauma-writing or religious trauma-writing condition. Depressive symptoms were assessed at baseline and again at one-month post writing. No significant association between EI and religiousness was found at baseline. Results indicated a three-way interaction among EI, trauma severity, and writing condition on depressive symptoms at follow-up. For the religious trauma-writing condition only, there was a significant difference between high- versus low-EI participants who experienced more severe trauma in depressive symptoms at follow-up, such that low-EI participants registered less depressive symptoms than high-EI participants; while there was no significant difference between low versus high EI for participants with less severe trauma. These findings encourage further investigation of the conditions under which religion may be a beneficial factor in trauma adaptation.

Assessment of psychiatric disorders among sex offenders: Prevalence and associations with criminal history.

BACKGROUND: Much of the research on the prevalence of psychiatric disorders among sex offenders has been conducted in the USA or Europe. Less is known about it in other regions, particularly in Asia. AIMS: The objective of this study is to determine the prevalence of psychiatric disorders among sex offenders in Taiwan and their associations with offender characteristics and criminal history. METHODS: Participants were randomly selected from men serving sentences in Taiwan's prison for serious sex offenders. Consenting men were assessed using the structured clinical interviews for DSM-IV-TR Axis I and II disorders. Demographics and criminal history were also recorded. RESULTS: Over two-thirds of the 68 participants met criteria for one or more lifetime Axis I disorders, and nearly 60% met criteria for one or more Axis II disorder. The higher the number of Axis I and cluster B personality disorders, the higher was the total number of convictions. CONCLUSIONS: Our study adds to the literature that suggests that psychiatric assessment is likely to have an important role in the management and treatment of sex offenders. The finding that multiple disorders are common in this group and associated with more convictions for sex offences suggests that failure to include psychiatric assessment in planning the management of sex offenders may increase the risk of recidivism.

Localization of luteinizing hormone receptor protein in the human ovary.

The luteinizing hormone receptor (LHR) plays a pivotal role during follicular development. Consequently, its expression pattern is of major importance for research and has clinical implications. Despite the accumulated information regarding LHR expression patterns, our understanding of its expression in the human ovary, specifically at the protein level, is incomplete. Therefore, our aim was to determine the LHR protein localization and expression pattern in the human ovary. We examined the presence of LHR by immunohistochemical staining of human ovaries and western blots of mural granulosa and cumulus cells aspirated during IVF treatments. We were not able to detect LHR protein staining in primordial or primary follicles. We observed equivocal positive staining in granulosa cells and theca cells of secondary follicles. The first appearance of a clear signal of LHR protein was observed in granulosa cells and theca cells of small antral follicles, and there was evidence of increasing LHR production as the follicles mature to the pre-ovulatory stage. After ovulation, LHR protein was ubiquitously produced in the corpus luteum. To confirm the expression pattern in granulosa cells and cumulus cells, we performed western blots and found that LHR expression was stronger in granulosa cells than in cumulus cells, with the later demonstrating low, but still significant, amounts of LHR protein. In summary, we conclude that LHR protein starts to appear on granulosa cells and theca cells of early antral follicles, and low but significant expression of LHR exists also in the cumulus cells. These results may have implications for the future design of clinical protocols and culture mediums for in vitro fertilization and especially in vitro maturation of oocytes.

Characterization of the human cumulus cell transcriptome during final follicular maturation and ovulation.

Cumulus expansion and oocyte maturation are central processes in ovulation. Knowledge gained from rodent and other mammalian models has revealed some of the molecular pathways associated with these processes. However, the equivalent pathways in humans have not been thoroughly studied and remain unidentified. Compact cumulus cells (CCs) from germinal vesicle cumulus oocyte complexes (COCs) were obtained from patients undergoing in vitro maturation (IVM) procedures. Expanded CCs from metaphase 2 COC were obtained from patients undergoing IVF/ICSI. Global transcriptome profiles of the samples were obtained using state-of-the-art RNA sequencing techniques. We identified 1746 differentially expressed (DE) genes between compact and expanded CCs. Most of these genes were involved in cellular growth and proliferation, cellular movement, cell cycle, cell-to-cell signaling and interaction, extracellular matrix and steroidogenesis. Out of the DE genes, we found 89 long noncoding RNAs, of which 12 are encoded within introns of genes known to be involved in granulosa cell processes. This suggests that unique noncoding RNA transcripts may contribute to the regulation of cumulus expansion and oocyte maturation. Using global transcriptome sequencing, we were able to generate a library of genes regulated during cumulus expansion and oocyte maturation processes. Analysis of these genes allowed us to identify important new genes and noncoding RNAs potentially involved in COC maturation and cumulus expansion. These results may increase our understanding of the process of oocyte maturation and could ultimately improve the efficacy of IVM treatment.

Exposure of fallopian tube epithelium to follicular fluid mimics carcinogenic changes in precursor lesions of serous papillary carcinoma.

OBJECTIVES: Ovulation-related inflammation is suspected to have a causal role in ovarian carcinogenesis, but there are no human models to study the molecular pathways. Our aim is to develop such an ex-vivo model based on human fallopian tube (FT) epithelium exposed to human follicular fluid (FF). METHODS: FT epithelium was dissociated from normal surgical specimens. FF was obtained from donors undergoing in-vitro fertilization. The cells were cultured on collagen-coated Transwells and incubated with FF for various periods of time. The transcriptomic changes resulting from FF treatment were profiled using Affymetrix expression arrays. Specific characteristics of the FT pre-cancerous lesions were studied using immunohistochemistry, immunofluorescence, RT-PCR and XTT assay. RESULTS: We show that FF exposure causes up-regulation of inflammatory and DNA repair pathways. Double stranded DNA breaks are induced. There is a minor increase in cell proliferation. TP53, which is the hallmark of the precursor lesion in-vivo, is accumulated. Levels of expression and secretion of Interleukin-8 are significantly increased. CONCLUSIONS: Our model addresses the main non-genetic risk factor for ovarian cancer, namely the impact of ovulation. This study demonstrates the biological implications of in-vitro exposure of human FT epithelial cells to FF. The model replicates elements characterizing the precursor lesions of ovarian cancer, and warrants further investigation of the linkage between repeated exposure to ovulation-related damage and accumulation of neoplastic changes.

Chemical dynamics of triacetylene formation and implications to the synthesis of polyynes in Titan's atmosphere.

For the last four decades, the role of polyynes such as diacetylene (HCCCCH) and triacetylene (HCCCCCCH) in the chemical evolution of the atmosphere of Saturn's moon Titan has been a subject of vigorous research. These polyacetylenes are thought to serve as an UV radiation shield in planetary environments; thus, acting as prebiotic ozone, and are considered as important constituents of the visible haze layers on Titan. However, the underlying chemical processes that initiate the formation and control the growth of polyynes have been the least understood to date. Here, we present a combined experimental, theoretical, and modeling study on the synthesis of the polyyne triacetylene (HCCCCCCH) via the bimolecular gas phase reaction of the ethynyl radical (CCH) with diacetylene (HCCCCH). This elementary reaction is rapid, has no entrance barrier, and yields the triacetylene molecule via indirect scattering dynamics through complex formation in a single collision event. Photochemical models of Titan's atmosphere imply that triacetylene may serve as a building block to synthesize even more complex polyynes such as tetraacetylene (HCCCCCCCCH).

The Involvement of Lumican in Human Ovulatory Processes.

Based on a previous global transcriptome sequencing project, we hypothesized that Lumican (LUM) might play a role in ovulatory processes. We sought to determine LUM gene expression under various conditions in human preovulatory follicles. The in vitro expression of LUM mRNA in mural (MGCs) and cumulus (CGCs) granulosa cells was characterized using quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical staining was used to identify human LUM expression in follicles at different developmental stages. Cell signaling studies were performed by treating human MGCs with human chorionic gonadotropin (hCG) and both, different stimulators and inhibitors to determine their effect on LUM expression by using qRT-PCR. Cell confluence studies were carried out to study the correlation between LUM expression and follicle cell proliferation. Follicular MGCs and CGCs of women undergoing in vitro fertilization (IVF) procedures due to endometriosis were analyzed for differences in LUM expression patterns by qRT-PCR. LUM mRNA expression was significantly higher in MGCs as compared to CGCs. In CGCs, LUM mRNA was higher in mature metaphase II (MII) oocytes than in germinal vesicle (GV) and metaphase I (MI) oocytes. LUM expression was significantly upregulated in response to hCG in cultured MGCs. Immunohistochemistry of human ovaries revealed LUM was mostly present in MGCs of large preovulatory and postovulatory follicles and absent from primordial follicles. Using pharmacological activators and inhibitors, we demonstrated that LUM induction by luteinizing hormone (LH)/hCG is carried through the mitogen-activated protein kinase (MEK) pathway. LUM expression was induced in high-density cell cultures in a confluence-dependent manner. MGCs from follicles of subjects with endometriosis exhibited reduced mRNA transcription levels compared to control subjects. Our study confirms that LUM is a newly discovered ovulatory gene. LUM might play an important role during the preovulatory period up until ovulation as well as in endometriosis infertility. A better understanding of LUM's role might provide potential new treatment paradigms for some types of female infertility.

Long-term drying of Mars by sequestration of ocean-scale volumes of water in the crust.

Geological evidence shows that ancient Mars had large volumes of liquid water. Models of past hydrogen escape to space, calibrated with observations of the current escape rate, cannot explain the present-day deuterium-to-hydrogen isotope ratio (D/H). We simulated volcanic degassing, atmospheric escape, and crustal hydration on Mars, incorporating observational constraints from spacecraft, rovers, and meteorites. We found that ancient water volumes equivalent to a 100 to 1500 meter global layer are simultaneously compatible with the geological evidence, loss rate estimates, and D/H measurements. In our model, the volume of water participating in the hydrological cycle decreased by 40 to 95% over the Noachian period (~3.7 billion to 4.1 billion years ago), reaching present-day values by ~3.0 billion years ago. Between 30 and 99% of martian water was sequestered through crustal hydration, demonstrating that irreversible chemical weathering can increase the aridity of terrestrial planets.

Mars Methane Sources in Northwestern Gale Crater Inferred From Back Trajectory Modeling.

During its first seven years of operation, the Sample Analysis at Mars Tunable Laser Spectrometer (TLS) on board the Curiosity rover has detected seven methane spikes above a low background abundance in Gale crater. The methane spikes are likely sourced by surface emission within or around Gale crater. Here, we use inverse Lagrangian modeling techniques to identify upstream emission regions on the Martian surface for these methane spikes at an unprecedented spatial resolution. Inside Gale crater, the northwestern crater floor casts the strongest influence on the detections. Outside Gale crater, the upstream regions common to all the methane spikes extend toward the north. The contrasting results from two consecutive TLS methane measurements performed on the same sol point to an active emission site to the west or the southwest of the Curiosity rover on the northwestern crater floor. The observed spike magnitude and frequency also favor emission sites on the northwestern crater floor, unless there are fast methane removal mechanisms at work, or either the methane spikes of TLS or the non-detections of ExoMars Trace Gas Orbiter cannot be trusted.

TP53 regulates human AlkB homologue 2 expression in glioma resistance to Photofrin-mediated photodynamic therapy.

BACKGROUND: Photodynamic therapy (PDT) is a promising adjuvant therapy in cancer treatment. However, cancers resistant to PDT, mediated through the efflux of photosensitisers by means of P-glycoprotein or ATP-binding cassette transporter proteins, have been reported. The DNA repair has also been suggested to be responsible for PDT resistance, but little is known about the repair pathways and mechanisms involved. Therefore, this study aimed to investigate the possible function of six major DNA repair mechanisms in glioma cells resistant to Photofrin-mediated PDT (Ph-PDT). METHODS: The U87 glioma cells relatively resistant to Ph-PDT were obtained by recovering the viable cells 3 h after PDT treatment. The mRNA and protein expression levels of DNA repair genes were evaluated by quantitative real-time reverse transcription-polymerase chain reaction and western blotting, respectively. Small-interfering RNA and chromatin-immunoprecipitation assays were used to further examine the relationship between AlkB, an alkylation repair homologue 2 (Escherichia coli) (ALKBH2) and Ph-PDT responsiveness, and transcription factors involved in ALKBH2 transcription. RESULTS: The ALKBH2 of DNA damage reversal was significantly increased at both mRNA and protein levels from 30 min to 48 h post-treatment with Ph-PDT. Conversely, down-regulating ALKBH2 expression enhances Ph-PDT efficiency. Furthermore, our data clearly show for the first time that tumour protein (TP53) is directly involved by binding to the promoter of ALKBH2 in mediating Ph-PDT resistance. CONCLUSION: C The DNA damage reversal mechanisms may have important functions in Ph-PDT resistance through the activation of ALKBH2 by TP53.

Elucidating Decorin's role in the preovulatory follicle.

BACKGROUND: DCN (decorin) is a proteoglycan known to be involved in regulating cell proliferation, collagen fibril organization and migration. In our global transcriptome RNA-sequencing approach to systematically identify new ovulation-associated genes, DCN was identified as one of the highly regulated genes. We therefore hypothesize that DCN may have a role in ovulatory processes such as cell migration and proliferation. AIM: To characterize the expression, regulation and function of the proteoglycan DCN in the human ovarian follicles during the preovulatory period. METHODS: The in-vivo expression of DCN mRNA in mural (MGCs) and cumulus (CGCs) granulosa cells was characterized using quantitative RT-PCR and western blot. A signaling study was performed by treating human MGCs cultures with gonadotropins and different stimulators and inhibitors to determine their effect on DCN expression by qRT- PCR and elucidate the pathways regulating these proteins. In a functional study, KGN granulosa cell line was used to study cell migration with a scratch assay. RESULTS: DCN mRNA expression was significantly higher in MGCs compared to CGCs. DCN mRNA was significantly higher in CGCs surrounding mature metaphase II (MII) oocytes compared to CGCs of germinal vesicle (GV) and metaphase I (MI) oocytes. hCG significantly increased DCN mRNA and protein expression levels in cultured MGCs. Using signal transduction activators and inhibitors, we demonstrated that DCN induction by LH/hCG is carried out via PKA, PKC, ERK/MEK, and PI3K pathways. We showed that DCN expression is also induced in high-density cell cultures, in a dose-dependent pattern. In addition, progesterone induced a significant increase in DCN secretion to the media. MGCs from follicles of endometriosis patients exhibited reduced (about 20% of) mRNA transcriptions levels compared to MGCs follicles of control patients. More significantly, we found that DCN has an inhibiting effect on KGN cell migration. CONCLUSIONS: Our study indicates that DCN is a unique ovulatory gene. Our findings support the hypothesis that DCN plays an important new role during the preovulatory period and ovulation, and stress its involvement in endometriosis infertility. A better understanding of DCN role in ovulation and endometriosis may provide treatment for some types of infertility.

Isotopic composition of the martian atmosphere.

Results from the neutral mass spectrometer carried on the aeroshell of Viking 1 show evidence for NO in the upper atmosphere of Mars and indicate that the isotopic composition of carbon and oxygen is similar to that of Earth. Mars is enriched in (15)N relative to Earth by about 75 percent, a consequence of escape that implies an initial abundance of nitrogen equivalent to a partial pressure of at least 2 millibars. The initial abundance of oxygen present either as CO(2) or H(2)O must be equivalent to an exchangeable atmospheric pressure of at least 2 bars in order to inhibit escape-related enrichment of (18)O.

Loss of atmosphere from Mars due to solar wind-induced sputtering.

Because Mars does not have a strong intrinsic magnetic field, the atmosphere is eroded by interactions with the solar wind. Early solar-system conditions enhanced the sputtering loss. It is calculated that approximately 3 bars of carbon dioxide (CO2) have been sputtered over the last 3.5 billion years. This significant increase over the previous estimate by Luhmann et al. of approximately 0.14 bar of CO2 is the result of the development of a more complete model. The model also predicts slightly greater loss of water--approximately 80 meters instead of the approximately 50 meters predicted by Luhmann et al. Because estimates of CO2 on early Mars range from 0.5 to 5 bars, the 0.14-bar estimate is insignificant but the approximately 3-bar estimate will have a large effect on our understanding of the planet's evolution.

Fixation of nitrogen in the prebiotic atmosphere.

Reactions between nitrogen and water in the air surrounding lightning discharges can provide an important source of nitric oxide even under conditions where oxygen is a minor atmospheric constituent. Estimates are given for the associated source of soluble nitrite and nitrate. It is shown that lightning and subsequent atmospheric chemistry can provide a source of nitrate for the primitive ocean as large as 106 tons of nitrogen per year, sufficient to fill the ocean to its present level of nitrate in less than 10(6) years.

Catalytic processes in the atmospheres of Earth and venus.

Photochemical processes in planetary atmospheres are strongly influenced by catalytic effects of minor constituents. Catalytic cycles in the atmospheres of Earth and Venus are closely related. For example, chlorine oxides (CIOx) act as catalysts in the two atmospheres. On Earth, they serve to convert odd oxygen (atomic oxygen and ozone) to molecular oxygen. On Venus they have a similar effect, but in addition they accelerate the reactions of atomic and molecular oxygen with carbon monoxide. The latter process occurs by a unique combination of CIOx catalysis and sulfur dioxide photosensitization. The mechanism provides an explanation for the very low extent of carbon dioxide decomposition by sunlight in the Venus atmosphere.

Solar control of the upper atmosphere of Triton.

If the upper atmosphere and ionosphere of Triton are controlled by precipitation of electrons from Neptune's magnetosphere as previously proposed, Triton could have the only ionosphere in the solar system not controlled by solar radiation. However, a new model of Triton's atmosphere, in which only solar radiation is present, predicts a large column of carbon atoms. With an assumed, but reasonable, rate of charge transfer between N2(+) and C, a peak C+ abundance results that is close to the peak electron densities measured by Voyager in Triton's ionosphere. These results suggest that Triton's upper atmospheric chemistry may thus be solar-controlled. Measurement of key reaction rate constants, currently unknown or highly uncertain at Triton's low temperatures, would help to clarify the chemical and physical processes occurring in Triton's atmosphere.

Rate of formation of the ClO dimer in the polar stratosphere: implications for ozone loss.

The gas-phase recombination of chlorine monoxide (ClO) has been investigated under the conditions of pressure and temperature that prevail in the Antarctic stratosphere during the period of maximum ozone (O3) disappearance. Measured rate constants are less than one-half as great as the previously accepted values. One-dimensional model calculations based on the new rate data indicate that currently accepted chemical mechanisms can quantitatively account for the observed O3 losses in late spring (17 September to 7 October). A qualitative assessment indicates that the existing mechanisms can only account for at most one-half of the measured O3 depletion in the early spring (28 August to 17 September), indicating that there may be additional catalytic cycles, besides those currently recognized, that destroy O3.

Ethane ocean on titan.

It is proposed that Saturn's satellite Titan is covered by an ocean one to several kilometers deep consisting mainly of ethane. If the ocean is in thermodynamic equilibrium with an atmosphere of 3 percent (mole fraction) methane, then its composition is roughly 70 percent ethane, 25 percent methane, and 5 percent nitrogen. Photochemical models predict that ethane is the dominant end product of methane photolysis so that the evolving ocean is both the source and sink for continuing photolysis. The coexisting atmosphere is compatible with Voyager data.