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Abiotic stressors threaten the survival mechanism of plant life on Earth. Phytohormones are one of the defensive molecules produced by plants to counteract destructive effects elicited by abiotic stresses. In recent years, melatonin has gained prime importance in plant research because of its regulatory role in abiotic stress tolerance. Melatonin plays a central role in interacting with other phytohormones such as auxin, gibberellin, cytokinin, abscisic acid, ethylene, brassinosteroids, jasmonic acid, salicylic acid and plant growth regulators like nitric oxide, polyamines, γ-aminobutyric acid and serotonin to regulate stress alleviation for maintaining basal growth under harsh environmental conditions. The precise understanding of intricate web of crosstalk mechanisms among different phytohormones and their interconnected networks in terms of synergistic and antagonistic actions is crucial for maintaining cellular dynamics under unfavorable conditions. Therefore, in the present review, we mainly focused on crosstalk regulatory circuits operated by melatonin with other phytohormones at both physiological and molecular levels and their responses under known abiotic stress environment. The biosynthesis, signaling pathway and efficacy of melatonin in various stress avoidance are also enumerated in this review. Indeed, it would not be presumptuous to hope that this review will be helpful for designing climate-smart crop cultivars in the forthcoming years using melatonin as the major stress mitigator and endogenous signaling molecule during stressful situations. [Display omitted] • Biosynthesis of melatonin in plants is more complex than in animals. • Melatonin receptor CAND2/PMTR1 participates in melatonin-mediated signal perception, involving mitogen activated protein kinase-signaling cascades to enhance stress tolerance. • Melatonin interacts with different phytohormones for conferring stress protection. • Melatonin and phytohormones crosstalk operates synergistically or antagonistically, depending on the nature and complexity of stress, plant type and surrounding environment. [ABSTRACT FROM AUTHOR]

Purpose: Black men in the United States suffer significantly higher incidence of and mortality from prostate cancer (PCa) than non-Black men. The cause of this disparity is multifactorial, though inequitable access to curative radiation modalities, including low-dose-rate (LDR) brachytherapy, may contribute. Despite this, there are few analyses evaluating the potential of different radiation therapies to mitigate outcome disparities. Therefore, we examined the clinical outcomes of Black and non-Black patients treated with definitive LDR brachytherapy for prostate cancer.Methods: Data were collected for all patients treated with definitive LDR brachytherapy between 2005 and 2018 on a retrospective IRB-approved protocol. Pearson Chi-Squared analysis was used to assess demographic and cancer differences between Black and non-Black cohorts. Freedom from biochemical failure (FFBF) was calculated using Kaplan-Meier analysis. Univariate and multivariate analyses were used to identify factors predictive of biochemical failure.Results: One hundred and sixty-seven patients were included in the analysis (Black: n=81 [48.5%]) with a median follow-up of 88.4 months. Black patients were from lower income communities (P <0.01), had greater social vulnerability (P <0.01), and had a longer interval between diagnosis and treatment (P = 0.011). Overall cumulative FFBF was 92.3% (95% CI: 87.8% - 96.8%) at 5 years and 87.7% (95% CI: 82.0% - 93.4%) at 7 years. There was no significant difference in FFBF in Black and non-Black patients (P = 0.114) and Black race was not independently predictive of failure (HR 1.51 [95% CI: 0.56 - 4.01]; P = 0.42). Overall survival was comparable between racial groups (P = 0.972). Only nadir PSA was significantly associated with biochemical failure on MVA (HR = 3.57 [95% CI: 02.44 - 5.22]; P <0.001).Conclusions: Black men treated with LDR brachytherapy achieved similar FFBF to their non-Black counterparts despite poorer socioeconomic status. This suggests that PCa treatment with brachytherapy may eliminate some disparities clinical outcomes. [ABSTRACT FROM AUTHOR]

Radiation therapy plays a major role in the treatment of lung cancer patients. However, cancer cells develop resistance to radiation. Tumor radioresistance is a complex multifactorial mechanism which may be dependent on DNA damage and repair, hypoxic conditions inside tumor microenvironment, and the clonal selection of radioresistant cells from the heterogeneous tumor site, and it is a major cause of treatment failure in non–small cell lung cancer (NSCLC). In the present investigation caveolin-1 (CAV-1) has been observed to be highly expressed in radiation resistant A549 lung cancer cells. CRISPR-Cas9 knockout of CAV-1 reverted the cells to a radio sensitive phenotype. In addition, CAV-1 overexpression in parental A549 cells, led to radiation resistance. Further, gene expression analysis of A549 parental, radiation resistant, and caveolin-1 overexpressed cells, exhibited overexpression of DNA repair genes RAD51B, RAD18, SOX2 cancer stem cell marker, MMPs, mucins and cytoskeleton proteins in resistant and caveolin-1 over expressed A549 cells, as compared to parental A549 cells. Bioinformatic analysis shows upregulation of BRCA1, Nuclear Excision DNA repair, TGFB and JAK/STAT signaling pathways in radioresistant and caveolin-1 overexpressed cells, which may functionally mediate radiation resistance. Immunohistochemistry data demonstrated heterogeneous expression of CAV-1 gene in human lung cancer tissues, which was analogous to its enhanced expression in human lung cancer cell line model and mouse orthotopic xenograft lung cancer model. Also, TCGA PanCancer clinical studies have demonstrated amplification, deletions and missense mutation in CAV-1 gene in lung cancer patients, and that CAV-1 alteration has been linked to poor prognosis, and poor survival in lung cancer patients. Interestingly, we have also optimized ELISA assay to measure caveolin-1 protein in the blood of A549 radiation resistant human xenograft preclinical mouse model and discovered higher level of caveolin-1 (950 pg/ml) in tumor bearing animals treated with radiation, as compared to xenograft with radiosensitive lung cancer cells (450 pg/ml). Thus, we conclude that caveolin-1 is involved in radio-resistance and contributes to tumor aggression, and it has potential to be used as prognostic biomarker for radiation treatment response, and tumor progression for precision medicine in lung cancer patients. [ABSTRACT FROM AUTHOR]

Key message: Melatonin enhanced arsenic (As) tolerance by inhibiting As bioaccumulation, modulating the expression of As transporters and phytohormone homeostasis, leading to efficient utilization of thiol machinery for sequestration and detoxification of this toxic metalloid. The present study was aimed at investigating the influence of exogenous melatonin on the regulation of endogenous plant growth regulators and their cumulative effects on metal(loid)-binding ligands in two contrasting indica rice cultivars, viz., Khitish (arsenic sensitive) and Muktashri (arsenic tolerant) under arsenic stress. Melatonin supplementation ameliorated arsenic-induced perturbations by triggering endogenous levels of gibberellic acid and melatonin, via up-regulating the expression of key biosynthetic genes like GA3ox, TDC, SNAT and ASMT. The endogenous abscisic acid content was also enhanced upon melatonin treatment by induced expression of the key anabolic gene, NCED3 and concomitant suppression of ABA8ox1. Enhanced melatonin content induced accumulation of higher polyamines (spermidine and spermine), together with up-regulation of SPDS and SPMS in Khitish, thereby modulating stress condition. On the contrary, melatonin escalated putrescine and spermidine levels in Muktashri, via enhanced expression of ADC and SAMDC. The role of melatonin appeared to be more prominent in Khitish, as evident from better utilization of thiol components like cysteine, GSH, non-protein thiols and phytochelatins, with higher GSH/GSSG ratio, despite down-regulated expression of corresponding thiol-metabolic genes (OsMT2 and OsPCS1) to deal with arsenic toxicity. The extent of arsenic bioaccumulation, which was magnified several folds, particularly in Khitish, was decreased upon melatonin application. Overall, our observation highlighted the fact that melatonin enhanced arsenic tolerance by inhibiting arsenic bioaccumulation, via modulating the expression levels of selected arsenic transporters (OsNramp1, OsPT2, OsPT8, OsLsi1) and controlling endogenous phytohormone homeostasis, leading to efficient utilization of thiol machinery for sequestration and detoxification of this toxic metalloid. [ABSTRACT FROM AUTHOR]

Drought is undoubtedly a major environmental constraint that negatively affects agricultural yield and productivity throughout the globe. Plants are extremely vulnerable to drought which imposes several physiological, biochemical and molecular perturbations. Increased generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in different plant organs is one of the inevitable consequences of drought. ROS and RNS are toxic byproducts of metabolic reactions and poise oxidative stress and nitrosative stress that are detrimental for plants. In spite of toxic effects, these potentially active radicals also play a beneficial role in mediating several signal transduction events that lead to plant acclimation and enhanced survival under harsh environmental conditions. The precise understanding of ROS and RNS signaling and their molecular paradigm with different phytohormones, such as auxin, gibberellin, cytokinin, abscisic acid, ethylene, brassinosteroids, strigolactones, jasmonic acid, salicylic acid and melatonin play a pivotal role for maintaining plant fitness and resilience to counteract drought toxicity. Therefore, the present review provides an overview of integrated systemic signaling between ROS, RNS and phytohormones during drought stress based on past and recent advancements and their influential role in conferring protection against drought-induced damages in different plant species. Indeed, it would not be presumptuous to hope that the detailed knowledge provided in this review will be helpful for designing drought-tolerant crop cultivars in the forthcoming times. [Display omitted] • Drought can cause serious threat to agricultural crop production, thereby affecting global food security. • Excess generation of ROS and RNS during drought act as a signal for phytohormone accumulation for ROS and RNS scavenging. • Crosstalk between ROS, RNS and phytohormone signaling plays pivotal role in understanding drought stress tolerance mechanism. • Drought-induced overproduction of ROS and RNS regulates stomatal closure. [ABSTRACT FROM AUTHOR]

• Arsenic (As) caused a marked inhibition in organic acid production and activity of enzymes of respiratory cycle in the susceptible variety, Khitish. • Arsenic exposure stimulated the accumulation of sugar in both the cultivars. • Exogenous melatonin supplementation improved the accumulation of organic acids in Khitish. • Exogenous melatonin supplementation significantly increased the activities of enzymes and corresponding gene expressions related to respiratory cycle and sugar metabolism. • The ameliorative effect of melatonin was more prominent in the susceptible variety as compared to the tolerant cultivar. The objective of the present investigation was to understand the impact of exogenously applied melatonin on mitochondrial respiration and sugar metabolism in two contrasting rice cultivars, viz., Khitish (arsenic-susceptible) and Muktashri (arsenic-tolerant) under arsenic-stress. Melatonin effectively restored the level of organic acids like pyruvic acid, malic acid and more particularly citric acid by 33 % in Khitish which were lowered during arsenic-stress, whereas their levels were further elevated in Muktashri to provide energy for defence against arsenic-induced injury. Arsenic-exposure led to a significant inhibition in enzyme activities as well as corresponding transcript level of key respiratory enzymes, viz., pyruvate dehydrogenase, citrate synthase, isocitrate dehydrogenase, succinate dehydrogenase and malate dehydrogenase, intriguingly more prominently in case of Khitish. Conversely, melatonin supplementation, irrespective of cultivars, considerably improved the activity of the above enzymes and corresponding gene expressions during stress, indicating acceleration in the rate of Krebs cycle. Melatonin supplementation also stimulated the accumulation of total soluble sugars by 62 % and 25 %, reducing sugars by 50 % and 44 % and non-reducing sugars by 75 % and 14 % in Khitish and Muktashri respectively, concomitant with higher activities of acid invertase, sucrose synthase and sucrose phosphate synthase enzymes, along with the expression of corresponding genes. Enhanced starch accumulation via regulation of alpha amylase and starch phosphorylase activities and gene expression, by melatonin also contributed towards better stress tolerance. Overall, this work illustrated the efficacy of melatonin in the regulation of representative organic acids and enzymes of respiratory cycle along with starch and sugar metabolism in rice cultivars under arsenic toxicity. [ABSTRACT FROM AUTHOR]

Reference 1 Leiser D, Samanta S, Eley J, Strauss J, Creed M, Kingsbury T, et al. (2021) Role of caveolin-1 as a biomarker for radiation resistance and tumor aggression in lung cancer. Please view the correct author order, affiliations, and citation here: Dominic Leiser SP 1 sp , Santanu Samanta SP 1 sp , Josh Strauss SP 2 sp , John Eley SP 2 sp , Michael Creed SP 3 sp , Tami Kingsbury SP 3 sp , Paul N. Staats SP 4 sp , Binny Bhandary SP 1 sp , Minjie Chen SP 1 sp , Tijana Dukic SP 1 sp , Sanjit Roy SP 1 sp , Javed Mahmood SP 1 sp , Zeljko Vujaskovic SP 1 sp , Hem D. Shukla SP 1 sp B 1 b Division of Translational Radiation Sciences (DTRS), Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, United States of America, B 2 b Department of Radiation Oncology, School of Medicine, Vanderbilt University, Nashville, TN, United States of America, B 3 b Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, United States of America, B 4 b Department of Pathology, University of Maryland, School of Medicine, Baltimore, MD, United States of America. [Extracted from the article]

The nonvolatile memory properties of the partially crystallized HfO2 charge storage layer are investigated using short-channel devices of gate length Lg down to 80 nm. Highly efficient two-bit and four-level device operation is demonstrated by channel hot electron injection programming and hot hole injection erasing for devices of Lg > 170 nm, although the reduction of the memory window is observed for devices of Lg < 170 nm. A memory window of 5.5 V, ten-year retention of Vth clearance larger than 1.5 V between adjacent levels, endurance for 105 programming/erasing cycles, and immunity to programming disturbances are demonstrated. Flash memory with partially crystallized HfO2 shows a larger memory window than HfO2 nanodot memory, assisted by the enhanced electron capture efficiency of an amorphous HfO2 matrix, which is lacking in other types of reported nanodot memory. The scalability, programming speed, Vth control for two-bit and four-level operation, endurance, and retention are also improved, compared with NROM devices that use a Si3N4 trapping layer. [ABSTRACT FROM AUTHOR]

• Arsenic and fluoride stimulated their co-uptake in rice seedlings. • Arsenic induced chloride channels. • Fluoride induced phosphate transporters. • Excessive accumulation of arsenic and fluoride triggered physiological injuries. • Combined stress suppressed the 'tolerant'-phenotype of Muktasri. The current study elucidates the uncharacterized biohazard associated with rice growth in arsenic and fluoride co-contaminated sites. Analysis of the arsenic-tolerant rice cultivar, Muktashri (known to restrict arsenic uptake) revealed that fluoride largely stimulated arsenic bioaccumulation in the stressed tissues and vice versa. Gene expression studies revealed that high arsenic uptake was facilitated by the fluoride-dependent up regulation of phosphate transporter2 (PT2) , PT8 and low silicon rice1 (Lsi1), and elevated fluoride accumulation was stimulated by the arsenic-mediated induction of chloride channels (CLC s). The endogenous accumulation of fluoride and arsenic increased reactive oxygen species (ROS), O 2 −, membrane peroxidation and arsenic localization within tissues. This inhibited plant growth by triggering chlorosis, electrolyte leakage, malondialdehyde production (due to high lipoxygenase activity), protein carbonylation, protease activity and methylglyoxal accumulation due to inhibited glyoxylase activity. Metabolic analysis showed inhibited proline biosynthesis along with increased channelization of glutathione towards phytochelatin synthase and glutathione-S-tranferase -dependent pathways. Inhibition of the antioxidant enzymes like catalase, ascorbate peroxidase and guaiacol peroxidase validated the inefficient scavenging of H 2 O 2 during combined stress. In silico analyses predicted the ecotoxicological risks of arsenic-fluoride complex formed during joint stress. Overall, our investigation illustrated the underlying mechanism of arsenic-fluoride co-uptake which resulted in complete suppression of the 'tolerant'-phenotype in Muktashri seedlings. [ABSTRACT FROM AUTHOR]

Purpose: Radiation injury to the bronchial tree is an important yet poorly understood potential side effect in lung stereotactic ablative radiation therapy (SAbR). We investigate the integration of virtual bronchoscopy in radiation therapy planning to quantify dosage to individual airways. We develop a risk model of airway collapse and develop treatment plans that reduce the risk of radiation-induced airway injury.Methods and Materials: Pre- and post-SAbR diagnostic-quality computerized tomography (CT) scans were retrospectively collected from 26 lung cancer patients. From each scan, the bronchial tree was segmented using a virtual bronchoscopy system and registered deformably to the planning CT. Univariate and stepwise multivariate Cox regressions were performed, examining factors such as age, comorbidities, smoking pack years, airway diameter, and maximum point dosage (Dmax). Logistic regression was utilized to formulate a risk function of segmental collapse based on Dmax and diameter. The risk function was incorporated into the objective function along with clinical dosage volume constraints for planning target volume (PTV) and organs at risk (OARs).Results: Univariate analysis showed that segmental diameter (P = .014) and Dmax (P = .007) were significantly correlated with airway segment collapse. Multivariate stepwise Cox regression showed that diameter (P = .015), Dmax (P < .0001), and pack/years of smoking (P = .02) were significant independent factors associated with collapse. Risk management-based plans enabled significant dosage reduction to individual airway segments while fulfilling clinical dosimetric objectives.Conclusion: To our knowledge, this is the first systematic investigation of functional avoidance in lung SAbR based on mapping and minimizing doses to individual bronchial segments. Our early results show that it is possible to substantially lower airway dosage. Such dosage reduction may potentially reduce the risk of radiation-induced airway injury, while satisfying clinically prescribed dosimetric objectives. [ABSTRACT FROM AUTHOR]

Reduced intensity conditioning (RIC) regimens decrease the risk for nonrelapse mortality (NRM) in adult patients undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies but increase the risk for relapse. The aim of this study was to compare the outcomes of fludarabine–total body irradiation (TBI) with fludarabine among patients with hematologic diseases. This retrospective study of 137 patients with different hematologic malignancies compared the outcomes of 63 patients who received a conventional RIC regimen with 2 days of IV busulfan (3.2 mg/kg/d × 2 days) and fludarabine with 74 patients who received the same regimen plus 400 cGy of fludarabine and busulfan (FB)-TBI divided in 2 doses over 1 day (200 cGy BID). Median follow-up was 4.62 years. The donors were either HLA-matched siblings (36%) or HLA-matched unrelated donors (64%). The FB-TBI showed trends toward improvement in progression-free survival (PFS) and overall survival (OS) over FB (5-year PFS rates 50% vs 34%, P =.06, and 5-year OS rate 53% vs 39%, P =.13). Acute graft-vs-host disease (aGVHD), relapse, and NRM were similar between the 2 groups. The 5-year cumulative incidence of chronic GVHD (cGVHD) was lower in the FB-TBI group compared with the FB group (29% vs 52%, P =.003). Multivariable analysis revealed that grade III-IV aGVHD was the only independent risk factor for worse OS (P =.001) in both groups. A high disease risk index was possibly associated with inferior OS (P =.07) in both groups. The FB-TBI is a safe and effective intensified RIC regimen for adult patients with hematologic malignancies. It predicted a lower risk for cGVHD and showed possibly improved PFS and OS compared with FB. [ABSTRACT FROM AUTHOR]

• Many head/neck squamous cell cancer patients develop recurrence or second primary. • Re-irradiation is a curative treatment option for these patients. • However, it is associated with significant risk of toxicity. • Pulsed Reduced Dose Rate radiation may reduce re-irradiation toxicity. Pulsed reduced dose rate (PRDR) radiation (RT) is a re-irradiation (Re-RT) technique that potentially overcomes dose/volume constraints in the setting of previous RT. There is minimal data for its use for recurrent or secondary primary head and neck squamous cell carcinoma (HNSCC). In this study, we report preliminary data from our institution of a consecutive cohort of HNSCC patients who received PRDR Re-RT. Nine patients received PRDR Re-RT from August 2020 to January 2023 and had analyzable data. Intensity modulated RT was used for treatment delivery and a wait time between 20 cGy arc/helical deliveries was used to achieve the effective low dose rate. Data collected included patient demographic information, prior interventions, diagnosis, radiation therapy dose and fractionation, progression free survival, overall survival, and toxicity rates. The median time to PRDR-RT from completion of initial RT was 13 months (range, 6–50 months). All but one patient underwent salvage surgery prior to PRDR-RT. The median follow-up after Re-RT was 7 months. The median OS from PRDR-RT was 7 months (range, 1–32 months). Median PFS was 7 months (range, 1–32 months). One patient (11.1 %) had acute grade 3 toxicity, and two patients (22.2 %) had late grade 3 toxicities. There were no grade 4+ toxicities. PRDR Re-RT is a feasible treatment strategy for patients with recurrent or second primary HNSCC. Initial findings from this retrospective review suggest reasonable survival outcomes and potentially improved toxicity; prospective data is needed to establish the safety and efficacy of this technique. [ABSTRACT FROM AUTHOR]

Summary: In the relapsed/refractory setting for treatment of large B‐cell lymphoma (LBCL), chimeric antigen receptor T‐cell (CAR‐T) therapy has emerged as an effective treatment modality. Patients often have aggressive disease that requires prompt treatment in the form of bridging therapy (BT) for disease stabilisation while CAR‐T cells are manufactured. Patients (n = 75) undergoing CAR‐T therapy infusion for LBCL at our institution were identified. A total of 52 (69·3%) received BT and 23 (30·7%) received no BT (NBT). BT modalities included systemic BT (SBT) in 28 patients, radiation BT (RBT) in 14, and high‐dose steroid BT (HDS) in 10. There was no difference in incidence of cytokine release syndrome or immune effector cell‐associated neurotoxicity syndrome between BT and NBT (P = 0·18 and P = 0·53 respectively). Prolonged cytopenias at Day 180 were more common in BT than NBT (50% vs. 13·3%, P = 0·04). The SBT and RBT subgroups had more cytopenias at Day 180 compared to the HDS and NBT subgroups (58·3% and 57·1% vs. 20% and 13·3% respectively, P = 0·04). Disease response at last follow‐up, progression‐free survival and overall survival were similar between BT, NBT, and BT subgroups. In summary, BT can be safely considered in patients undergoing CAR‐T therapy. However, those undergoing BT with SBT or RBT are at higher risk of prolonged cytopenias after CAR‐T therapy. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the trapping properties of high κ material as the charge storage layer in non-volatile flash memory devices using a two-dimensional device simulator, Medici. The high κ material is sandwiched between two silicon oxide layers, resulting in the Silicon-Oxide-High κ-Oxide-Silicon (SOHOS) structure. The trap energy levels of the bulk electron traps in high κ material were determined. The programming and erasing voltage and time using Fowler Nordheim tunneling were estimated by simulation. The effect of deep level traps on erasing was investigated. Also, the effect of bulk traps density, thickness of block oxide and thickness of high κ material on the threshold voltage of the device was simulated. [Copyright &y& Elsevier]

Background: Pancreatic cancer (PC) is the fourth-most-deadly cancer in the United States with a 5-year survival rate of only 8%. Unfortunately, only 10–20% of PC patients are candidates for surgery, with the vast majority of patients with locally-advanced disease undergoing chemotherapy and/or radiation therapy (RT). Current treatments are clearly inadequate and novel strategies are crucially required. We investigated a novel tripartite treatment (combination of tumor targeted hyperthermia (HT), radiation therapy (RT), and immunotherapy (IT)) to alter immunosuppressive PC-tumor microenvironment (TME). (2). Methods: In a syngeneic PC murine tumor model, HT was delivered before tumor-targeted RT, by a small animal radiation research platform (SARRP) followed by intraperitoneal injections of cytotoxic T-cell agonist antibody against OX40 (also known as CD134 or Tumor necrosis factor receptor superfamily member 4; TNFRSF4) that can promote T-effector cell activation and inhibit T-regulatory (T-reg) function. (3). Results: Tripartite treatment demonstrated significant inhibition of tumor growth (p < 0.01) up to 45 days post-treatment with an increased survival rate compared to any monotherapy. Flow cytometric analysis showed a significant increase (p < 0.01) in cytotoxic CD8 and CD4+ T-cells in the TME of the tripartite treatment groups. There was no tripartite-treatment-related toxicity observed in mice. (4). Conclusions: Tripartite treatment could be a novel therapeutic option for PC patients. [ABSTRACT FROM AUTHOR]

Non-ablative or mild hyperthermia (HT) has been shown in preclinical (and clinical) studies as a localized radiosensitizer that enhances the tumoricidal effects of radiation. Most preclinical in vivo HT studies use subcutaneous tumor models which do not adequately represent clinical conditions (e.g. proximity of normal/critical organs) or replicate the tumor microenvironment—both of which are important factors for eventual clinical translation. The purpose of this work is to demonstrate proof-of-concept of locoregional radiosensitization with superficially applied, radiofrequency (RF)-induced HT in an orthotopic mouse model of prostate cancer. In a 4-arm study, 40 athymic male nude mice were inoculated in the prostate with luciferase-transfected human prostate cancer cells (PC3). Tumor volumes were allowed to reach 150–250 mm3 (as measured by ultrasound) following which, mice were randomized into (i) control (no intervention); (ii) HT alone; (iii) RT alone; and (iv) HT + RT. RF-induced HT was administered (Groups ii and iv) using the Oncotherm LAB EHY-100 device to achieve a target temperature of 41 °C in the prostate. RT was administered ~30 min following HT, using an image-guided small animal radiotherapy research platform. In each case, a dual arc plan was used to deliver 12 Gy to the target in a single fraction. One animal from each cohort was euthanized on Day 10 or 11 after treatment for caspase-9 and caspase-3 Western blot analysis. The inoculation success rate was 89%. Mean tumor size at randomization (~16 days post-inoculation) was ~189 mm3. Following the administration of RT and HT, mean tumor doubling times in days were: control = 4.2; HT = 4.5; RT = 30.4; and HT + RT = 33.4. A significant difference (p = 0.036) was noted between normalized nadir volumes for the RT alone (0.76) and the HT + RT (0.40) groups. Increased caspase-3 expression was seen in the combination treatment group compared to the other treatment groups. These early results demonstrate the successful use of external mild HT as a localized radiosensitizer for deep-seated tumors. We successfully demonstrated the feasibility of administering external mild HT in an orthotopic tumor model and demonstrated preclinical proof-of-concept of HT-based localized radiosensitization in prostate cancer radiotherapy. [ABSTRACT FROM AUTHOR]

Purpose/objectives: Radiation-induced erectile-dysfunction (RiED) is one of the most common side effects of radiation therapy (RT) and significantly reduces the quality of life (QoL) of cancer patients. Approximately 50% of prostate cancer patients experience RiED within 3 to 5 years after completion of RT. A series of vascular, muscular, and neurogenic injuries after prostate RT lead to RiED; however, the precise role of RT-induced neurogenic injury in RiED has not been fully established. The cavernous nerves (CN) are postganglionic parasympathetic nerves located beside the prostate gland that assist in penile erection. This study was designed to investigate the role of CN injury, tissue damage, and altered signaling pathways in an RiED rat model.Methods and Materials: Male rats were exposed to a single dose of 25 Gy prostate-confined RT. Erectile function was evaluated by intracavernous pressure (ICP) measurements conducted both 9 and 14 weeks after RT. Neuronal injury was evaluated in the CN using quantitative polymerase chain reaction, conduction studies, transmission electron microscopy, and immunoblotting. Masson trichrome staining was performed to elucidate fibrosis level in penile tissues.Results: There were significant alterations in the ICP (P<.0001) of RT rats versus non-RT rats. TEM analysis showed decreased myelination, increased microvascular damage, and progressive axonal atrophy of the CN fibers after RT. Electrophysiologic analysis showed significant impairment of the CN conduction velocity after RT. RT also significantly increased RhoA/Rho-associated protein kinase 1 (ROCK1) mRNA and protein expression. In addition, penile tissue showed increased apoptosis and fibrosis 14 weeks after RT.Conclusions: RT-induced CN injury may contribute to RiED; this is therefore a rationale for developing novel therapeutic strategies to mitigate CN and tissue damage. Moreover, further investigation of the RhoA/ROCK pathway's role in mitigating RiED is necessary. [ABSTRACT FROM AUTHOR]

Background. Tuberculosis (TB) remains a global public health problem with known gender-related disparities. We reviewed the quantitative evidence for gender-related differences in accessing TB services from symptom onset to treatment initiation. Methods. Following a systematic review process, we: searched 12 electronic databases; included quantitative studies assessing gender differences in accessing TB diagnostic and treatment services; abstracted data; and assessed study validity. We defined barriers and delays at the individual and provider/system levels using a conceptual framework of the TB care continuum and examined gender related differences. Results. Among 13,448 articles, 137 were included: many assessed individual-level barriers (52%) and delays (42%), 76% surveyed persons presenting for care with diagnosed or suspected TB, 24% surveyed community members, and two thirds were from African and Asian regions. Many studies reported no gender differences. Among studies reporting disparities, women faced greater barriers (financial: 64% versus 36%; physical: 100% versus 0%; stigma: 85% versus 15%; health literacy: 67% versus 33%; and provider-/system-level: 100% versus 0%) and longer delays (presentation to diagnosis: 45% versus 0%) than men. Conclusions. Many studies found no quantitative gender-related differences in barriers and delays limiting access to TB services. When differences were identified, women experienced greater barriers and longer delays than men. [ABSTRACT FROM AUTHOR]

Targeted therapies like vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) are the first-choice treatment in several types of cancers. We aim to determine the comparative risk of bleeding events associated with the VEGFR-TKIs through a network meta-analysis. Published data search up to November 2018 reporting bleeding in cancer patients treated with VEGFR-TKIs was performed. The primary outcome was presence of hemorrhagic events at the end of the trial. Bleeding as a side-effect profile was examined for eleven VEGFR-TKIs (Apatinib, Brivanib, Cabozantinib, Lenvatinib, Motesanib, Nintedanib, Pazopanib, Regorafenib, Sorafenib, Sunitinib and Vandetanib). Network meta-analysis based on random effects model estimating Odds Ratio (OR) with 95 % confidence interval (CI), compared the risk of bleeding events among the VEGFR-TKIs with respect to placebo control conditions. Fifty Randomized Clinical Trials (RCTs) including 16,753 cancer patients were included in this analysis. Twenty studies compared VEGFR-TKIs with placebo, the remaining studies compared VEGFR-TKIs with the standard chemotherapeutic regimen. VEGFR-TKIs were associated with increased incidence of all-grade hemorrhagic events in comparison to control (standard chemotherapy and/or placebo) (OR = 1.79; 95 % CI 1.50–2.13, p-value <0.0001) and placebo (OR = 1.50; 95 % CI 1.16–1.93, p-value = 0.1). However, there was no difference in high-grade bleeding in patients treated with VEGFR-TKI in comparison to control (OR = 1.22; 95 % CI 0.87–1.71, p-value 0.74) or placebo alone (OR = 1.05; 95 % CI 0.65–1.70, p-value 0.73). Among individual VEGFR-TKIs, Sunitinib (OR = 3.31, 95 % CI 2.34–4.69) and Regorafenib (OR = 2.92, 95 % CI 1.50–5.71) were associated with higher risk of hemorrhagic events in comparison to placebo. VEGR-TKIs, particularly Sunitinib and Regorafenib appear to be associated with increased risk of bleeding incidence. PROSPERO CRD42017056406. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) has the highest mortality rate amongst all other cancers in both men and women, with a one-year relative survival rate of 20%, and a five-year relative survival rate of 8% for all stages of PC combined. The Whipple procedure, or pancreaticoduodenectomy, can increase survival for patients with resectable PC, however, less than 20% of patients are candidates for surgery at time of presentation. Most of the patients are diagnosed with advanced PC, often with regional and distant metastasis. In these advanced cases, chemotherapy and radiation have shown limited tumor control, and PC continues to be refractory to treatment and results in a poor survival outcome. In recent years, there has been intensive research on checkpoint inhibitor immunotherapy for PC, however, PC is characterized with dense stromal tissue and a tumor microenvironment (TME) that is highly immunosuppressive, which makes immunotherapy less effective. Interestingly, when immunotherapy is combined with radiation therapy (RT) and loco-regional hyperthermia (HT), it has demonstrated enhanced tumor responses. HT improves tumor killing via a variety of mechanisms, targeting both the tumor and the TME. Targeted HT raises the temperature of the tumor and surrounding tissues to 42–43 °C and makes the tumor more immunoresponsive. HT can also modulate the immune system of the TME by inducing and synthesizing heat shock proteins (HSP), which also activate an anti-tumor response. It is well known that HT can enhance RT-induced DNA damage in cancer cells and simultaneously help to oxygenate hypoxic regions. Thus, it is envisaged that combined HT and RT might have immunomodulatory effects in the PC-TME, making PC more responsive to immunotherapies. Moreover, the combined tripartite approach of immunotherapy, RT, and HT could reduce the overall toxicity associated with each individual therapy, while concomitantly enhancing the immunotherapeutic effect of overall individual therapies to treat local and metastatic PC. Thus, the use of a tripartite combinatorial approach could be promising and more efficacious than monotherapy or dual therapy to treat and increase the survival of the PC patients. [ABSTRACT FROM AUTHOR]