Prostatic irradiation-induced sexual dysfunction: A review and multidisciplinary guide to management in the radical radiotherapy era (Part II on Urological Management)

Prostate cancer is the most common malignancy in men and the second leading cause of cancer-related death in men. Radiotherapy is a curative option that is administered via external beam radiation, brachytherapy, or in combination. Sexual dysfunction is a common toxicity following radiotherapy, similar to men undergoing radical prostatectomy, but the etiology is different. The pathophysiology of radiation-induced sexual dysfunction is multi-factorial, and the toxicity is a major cause of impaired quality of life among long-term prostate cancer survivors. Management of a patient’s sexual function during and after radiotherapy requires multidisciplinary coordination of care between radiation oncology, urology, psychiatry, pharmacy, and dermatology. This review provides a framework for clinicians to better understand prostatic radiotherapy-induced sexual dysfunction diagnosis, evaluation, and a patient-centered approach to toxicity preventive strategies and management.     

Shared ancestral polymorphisms and chromosomal rearrangements as potential drivers of local adaptation in a marine fish

Gene flow has tremendous importance for local adaptation, by influencing the fate of de novo mutations, maintaining standing genetic variation and driving adaptive introgression. Furthermore, structural variation as chromosomal rearrangements may facilitate adaptation despite high gene flow. However, our understanding of the evolutionary mechanisms impending or favouring local adaptation in the presence of gene flow is still limited to a restricted number of study systems. In this study, we examined how demographic history, shared ancestral polymorphism, and gene flow among glacial lineages contribute to local adaptation to sea conditions in a marine fish, the capelin (<i>Mallotus villosusi>). We first assembled a 490‐Mbp draft genome of <i>M. villosusi> to map our RAD sequence reads. Then, we used a large data set of genome‐wide single nucleotide polymorphisms (25,904 filtered SNPs) genotyped in 1,310 individuals collected from 31 spawning sites in the northwest Atlantic. We reconstructed the history of divergence among three glacial lineages and showed that they probably diverged from 3.8 to 1.8 million years ago and experienced secondary contacts. Within each lineage, our analyses provided evidence for large <i>N_ei> and high gene flow among spawning sites. Within the Northwest Atlantic lineage, we detected a polymorphic chromosomal rearrangement leading to the occurrence of three haplogroups. Genotype–environment associations revealed molecular signatures of local adaptation to environmental conditions prevailing at spawning sites. Our study also suggests that both shared polymorphisms among lineages, resulting from standing genetic variation or introgression, and chromosomal rearrangements may contribute to local adaptation in the presence of high gene flow.     

Fungal communities living within leaves of native Hawaiian dicots are structured by landscape‐scale variables as well as by host plants

A phylogenetically diverse array of fungi live within healthy leaf tissue of dicotyledonous plants. Many studies have examined these endophytes within a single plant species and/or at small spatial scales, but landscape‐scale variables that determine their community composition are not well understood, either across geographic space, across climatic conditions, or in the context of host plant phylogeny. Here, we evaluate the contributions of these variables to endophyte beta diversity using a survey of foliar endophytic fungi in native Hawaiian dicots sampled across the Hawaiian archipelago. We used Illumina technology to sequence fungal ITS1 amplicons to characterize foliar endophyte communities across five islands and 80 host plant genera. We found that communities of foliar endophytic fungi showed strong geographic structuring between distances of 7 and 36 km. Endophyte community structure was most strongly associated with host plant phylogeny and evapotranspiration, and was also significantly associated with NDVI, elevation and solar radiation. Additionally, our bipartite network analysis revealed that the five islands we sampled each harboured significantly specialized endophyte communities. These results demonstrate how the interaction of factors at large and small spatial and phylogenetic scales shapes fungal symbiont communities.     

Hysteresis in poly‐2′‐deoxycytidine i‐motif folding is impacted by the method of analysis as well as loop and stem lengths

In DNA, i‐motif (iM) folds occur under slightly acidic conditions when sequences rich in 2′‐deoxycytidine (dC) nucleotides adopt consecutive dC self base pairs. The pH stability of an iM is defined by the midpoint in the pH transition (pH_T) between the folded and unfolded states. Two different experiments to determine pH_T values via circular dichroism (CD) spectroscopy were performed on poly‐dC iMs of length 15, 19, or 23 nucleotides. These experiments demonstrate two points: (1) pH_T values were dependent on the titration experiment performed, and (2) pH‐induced denaturing or annealing processes produced isothermal hysteresis in the pH_T values. These results in tandem with model iMs with judicious mutations of dC to thymidine to favor particular folds found the hysteresis was maximal for the shorter poly‐dC iMs and those with an even number of base pairs, while the hysteresis was minimal for longer poly‐dC iMs and those with an odd number of base pairs. Experiments to follow the iM folding via thermal changes identified thermal hysteresis between the denaturing and annealing cycles. Similar trends were found to those observed in the CD experiments. The results demonstrate that the method of iM analysis can impact the pH_T parameter measured, and hysteresis was observed in the pH_T and <i>Ti>_m values.     

Hominid Footprints in Recent Volcanic Ash: New Interpretations from Hawaii Volcanoes National Park

Recent archeological research at Hawaii Volcanoes National Park indicates that the story behind the imprinting of at least 1773 human footprints preserved in the Ka’u Desert ash is more complex than originally thought. Footprint impressions found in desert ash layers were previously believed to have been created by the army of the Hawaiian Chief Keoua on its way back from battle in 1790. When Kilauea is said to have erupted, apparently suffocating one group, the others made it out alive, apparently leaving their footprints in the then-wet ash, which evidently dried and hardened. These features have since been preserved, often under layers of volcanic sand. This simple explanation of an event still remembered in oral tradition, is not supported by the geologic evidence and the recent discovery of hundreds of archaeological features which indicate much more prehistoric activity in the area for at least two centuries prior to 1790. This suggests other people contributed to the footprints preserved in the desert ash.     

Dual character of GABA action on Cl–-transport by the reconstituted Cl–/-ATPase from rat brain

Abstract

The Cl^–/ipt><img src="/na101/home/literatum/publisher/tandf/journals/content/irst20/2018/irst20.v038.i04/10799893.2018.1494741/20181127/images/irst_a_1494741_ilm0002.gif" alt=" />ipt><img src="//:0" alt=" class="no-mml-formula" data-formula-source="{"type" : "image", "src" : "/na101/home/literatum/publisher/tandf/journals/content/irst20/2018/irst20.v038.i04/10799893.2018.1494741/20181127/images/irst_a_1494741_ilm0002.gif"}" />-ATPase from the plasma membranes of animal brains is an ATP-consuming Cl^–-transporting ATPase P-type that is structurally coupled to GABA_A receptors. The aim of work was to study the GABA effect on Cl^– transport across liposomal membranes by the reconstituted ATPase under various conditions (i.e. in the absence and in the presence of ATP in the incubation medium). We reconstituted the affinity<i>-i>purified enzyme in the liposomes with a fluorescent dye for Cl^–. The Cl^–-transport in proteoliposomes was evaluated from variations in fluorescence. Native-PAGE of the purified enzyme preparation, as well as western blot analysis with an antibody against the GABA_AR β3 subunit, showed one band with a molecular mass of 300?kDa. The addition of GABA (100?μM) quickly resulted (1–3?s) in an increase in the Cl^– influx into proteoliposomes. The application of ATP (3?mM) resulted in a gradual increase in the Cl^– inflow into the proteoliposomes at 0.5–4?min. Vanadate (10?μM) did not change the GABA-induced Cl^– inflow into the liposomes, but completely inhibited the ATP-dependent Cl^– input. Under conditions where Cl^– was previously loaded into proteoliposomes by ATP-dependent Cl^– input, the addition of GABA to the incubation medium caused a short-lasting Cl^– efflux from the proteoliposomes. However, an additional long-time incubation of these proteoliposomes resulted in the restoration of Cl^– accumulation. Pentobarbital, propofol, or diazepam elevate and picrotoxin or furosemide eliminate the effect of GABA on the Cl^–-transport processes. These findings indicate a dual nature of GABA action on the Cl^–/ipt><img src="/na101/home/literatum/publisher/tandf/journals/content/irst20/2018/irst20.v038.i04/10799893.2018.1494741/20181127/images/irst_a_1494741_ilm0003.gif" alt=" />ipt><img src="//:0" alt=" class="no-mml-formula" data-formula-source="{"type" : "image", "src" : "/na101/home/literatum/publisher/tandf/journals/content/irst20/2018/irst20.v038.i04/10799893.2018.1494741/20181127/images/irst_a_1494741_ilm0003.gif"}" />-ATPase.     

Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTOR signaling pathway

Prostate cancer (CaP) is the second leading malignancy in men. The role of epithelial cell adhesion molecule (EpCAM), also known as CD326, in CaP progression and therapeutic resistance is still uncertain. Here, we aimed to investigate the roles of EpCAM in CaP metastasis and chemo/radioresistance. Expression of EpCAM in CaP cell lines and human CaP tissues was assessed using immunofluorescence and immunohistochemistry, respectively. EpCAM was knocked down (KD) in PC-3, DU145 and LNCaP-C4-2B cells using small interfering RNA (siRNA), and KD results were confirmed by confocal microscope, Western blotting and quantitative real time polymerase chain reaction (qRT-PCR). Cell growth was evaluated by proliferation and colony formation assays. The invasive potential was assessed using a matrigel chamber assay. Tumorigenesis potential was measured by a sphere formation assay. Chemo-/radiosensitivity were measured using a colony formation assay. Over-expression of EpCAM was found in primary CaP tissues and lymph node metastases including cancer cells and surrounding stromal cells. KD of EpCAM suppressed CaP proliferation and invasive ability, reduced sphere formation, enhanced chemo-/radiosensitivity, and down-regulated E-cadherin, p-Akt, p-mTOR, p-4EBP1 and p-S6K expression in CaP cells. Our findings suggest that EpCAM plays an important role in CaP proliferation, invasion, metastasis and chemo-/radioresistance associated with the activation of the PI3K/Akt/mTOR signaling pathway and is a novel therapeutic target to sensitize CaP cells to chemo-/radiotherapy.     

SHORT-TERM IMPACTS OF FORMULATIONS OF BACILLUS THURINGIENSIS VAR. ISRAELENSIS DE BARJAC AND THE ORGANOPHOSPHATE TEMEPHOS,USED IN BLACKFLY (DIPTERA: SIMULIIDAE) CONTROL,ON RHEOPHILIC BENTHIC MACROINVERTEBRATES IN THE MIDDLE ORANGE RIVER,SOUTH AFRICA

Summary

The impacts of larvicides used in the control of blackflies (Diptera: Simuliidae) on macroinvertebrates in the stones-in-current biotope were assessed during 8 field trials in the middle Orange River, South Africa. Two <i>Bacillus thuringiensisi> var. <i>israelensis (B.t.i.)i> products (Vectobac^R 12AS and Teknar^R HP-D) and the organophosphate temephos (Abate^R 200EC) were applied at recommended and high dosages to simulate “operational” and “worst-possible” scenario's respectively. Mortality was evaluated either by direct counting of invertebrates on stones before and after application, or by ranking invertebrates on a 4-point relative abundance scale before and after application. In addition, the re-appearance of benthic invertebrate population densities after temephos application was examined.

At the recommended dosage (1.2 ppm/10 min), <i>B.t.i.i> significantly reduced blackfly larval numbers (P<0.001) and those of the chironomid <i>Rheotanytarsus fuscusi> Freeman (P<0.05). At high dosage (20 ppm/10 min), numbers of the filter-feeding mayfly <i>Tricorythus discolori> (Burmeister) (P<0.01) and the chironomid <i>Cardiocladiusi> sp. (P<0.05) were also significantly reduced. No <i>Simuliumi> predators were directly affected by <i>B.t.i.i>, but there were indications of food shortage amongst Hydropsychidae and Hirudinea.

Temephos caused significant reductions in the relative abundance of 5 taxa at 0.05 ppm, 3 to 6 taxa at 0.1 ppm, and 9 taxa at 1.0 ppm (P<0.05). “Non-target” organisms which were most affected included the chironomid <i>R. fuscusi>, the mayflies <i>Baetis glaucusi> Agnew and <i>Choroterpes elegansi> Barnard, and the caddisflies <i>Cheumatopsyche thomassetii> Ulmer and <i>Amphipsyche scottaei> Kimmins. The mayfly <i>T. discolori> was tolerant of temephos, even at high dosage (1.0 ppm/10 min). In winter, most taxa re-appeared within 19 days, and population densities were back to pre-treatment levels within 35 days.

It is concluded that good reduction of blackfly populations may be obtained with minimal <i>directi> impact on the “non-target” fauna, provided recommended dosages of temephos are not exceeded. Overdosing with temephos may result in high mortality of “non-target” organisms, including blackfly predators, and should be avoided.     

PA-CRM: A continuous reassessment method for pediatric phase I oncology trials with concurrent adult trials

Pediatric phase I trials are usually carried out after the adult trial testing the same agent has started, but not completed yet. As the pediatric trial progresses, in light of the accrued interim data from the concurrent adult trial, the pediatric protocol often is amended to modify the original pediatric dose escalation design. In practice, this is done frequently in an ad hoc way, interrupting patient accrual and slowing down the trial. We developed a pediatric-continuous reassessment method (PA-CRM) to streamline this process, providing a more efficient and rigorous method to find the maximum tolerated dose for pediatric phase I oncology trials. We use a discounted joint likelihood of the adult and pediatric data, with a discount parameter controlling information borrowing between pediatric and adult trials. According to the interim adult and pediatric data, the discount parameter is adaptively updated using the Bayesian model averaging method. Numerical study shows that the PA-CRM improves the efficiency and accuracy of the pediatric trial and is robust to various model assumptions.     

Monoclonal antibody against the poly-γ-d-glutamic acid capsule of Bacillus anthracis protects mice from enhanced lethal toxin activity due to capsule and anthrax spore challenge

id="absSec_1">Background

The poly-γ-d-glutamic acid (PGA) capsule, a major virulence factor of Bacillus anthracis, protects bacilli from immune surveillance and allows its unimpeded growth in the host. Recently, the importance of the PGA in the pathogenesis of anthrax infection has been reported. The PGA capsule is associated with lethal toxin (LT) in the blood of experimentally infected animals and enhances the cytotoxicity of LT.

id="absSec_2">Methods

To investigate the role of anti-PGA Abs on progression of anthrax infection, two mouse anti-PGA mAbs with K_d values of 0.8 μM and 2.6 μM respectively were produced and in silico three dimensional (3D) models of mAbs with their cognitive PGA antigen complex were analyzed.

id="absSec_3">Results

Anti-PGA mAbs specifically bound encapsulated B. anthracis H9401 and showed opsonophagocytosis activity against the bacteria with complement. The enhancement effect of PGA on LT-mediated cytotoxicity was confirmed ex vivo using mouse bone marrow-derived macrophages and was effectively inhibited by anti-PGA mAb. Passive immunization of mAb completely protected mice from PGA-enhanced LT toxicity and partially rescued mice from anthrax spore challenges. 3D structure models of these mAbs and PGA complex support specific interactions between CDR and cognitive PGA. These results indicate that mouse mAb against PGA capsule prevents the progress of anthrax disease not only by eliminating the vegetative form of encapsulated B. anthracis but also by inhibiting the enhanced cytotoxic activity of LT by PGA through specific binding with PGA capsule antigen.

id="absSec_4">General significance

Our results suggest a potential role for PGA antibodies in preventing and treating anthrax infection.