Probiotic Lactobacillus spp. improves Drosophila memory by increasing lactate dehydrogenase levels in the brain mushroom body neurons.

Probiotics are live microorganisms that offer potential benefits to their hosts and can occasionally influence behavioral responses. However, the detailed mechanisms by which probiotics affect the behavior of their hosts and the underlying biogenic effects remain unclear. Lactic acid bacteria, specifically Lactobacillus spp. are known probiotics. Drosophila melanogaster, commonly known as the fruit fly, is a well-established model organism for investigating the interaction between the host and gut microbiota in translational research. Herein, we showed that 5-day administration of Lactobacillus acidophilus (termed GMNL-185) or Lacticaseibacillus rhamnosus (termed GMNL-680) enhances olfactory-associative memory in Drosophila. Moreover, a combined diet of GMNL-185 and GMNL-680 demonstrated synergistic effects on memory functions. Live brain imaging revealed a significant increase in calcium responses to the training odor in the mushroom body ß and γ lobes of flies that underwent mixed feeding with GMNL-185 and GMNL-680. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and whole-mount brain immunohistochemistry revealed significant upregulation of lactate dehydrogenase (LDH) expression in the fly brain following the mixed feeding. Notably, the genetic knockdown of Ldh in neurons, specifically in mushroom body, ameliorated the beneficial effects of mixed feeding with GMNL-185 and GMNL-680 on memory improvement. Altogether, our results demonstrate that supplementation with L. acidophilus and L. rhamnosus enhances memory functions in flies by increasing brain LDH levels.

Outcomes of Breast-Conserving Therapy in Patients With Inflammatory Breast Cancer: A Meta-Analysis.

INTRODUCTION: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer. Currently, patients who respond to neoadjuvant chemotherapy (NAC) are treated with mastectomy and axillary lymph node dissection. This study aimed to synthesize real-world data to evaluate the feasibility of breast-conserving therapy (BCT), sentinel lymph node (SLN), and sentinel lymph node biopsy (SLNB) for patients with IBC who respond to NAC. METHODS: PubMed, Embase, and Cochrane Library databases were searched for relevant articles. Clinical studies that compared mastectomy with BCT for IBC treatment were reviewed. The primary outcomes were local recurrence rate and 5-y survival rate in patients with IBC who responded to NAC. Furthermore, the SLN detection rate and false-negative rate (FNR) for SLNB were also evaluated. RESULTS: In the final analysis, 17 studies were included. The pooled estimates of the local recurrence rate for mastectomy and no surgical intervention were 18.6% and 15.9%, respectively (P = 0.956). Five-y survival was similar for mastectomy, partial mastectomy, and no surgical intervention (45.8%, 57.1%, and 39.4%, respectively). The pooled estimates of the SLN detection rate and FNR for SLNB were 81.9% and 21.8%, respectively. CONCLUSIONS: Among patients with IBC who respond to NAC, the local recurrence and 5-y survival rates in those undergoing BCT are noninferior to the rates in those undergoing mastectomy; therefore, BCT could be a feasible option for surgical management. However, a poor SLN detection rate and a high FNR were found in patients undergoing SLNB. Further large-scale clinical studies are required to confirm our findings.

Thermosensation and Temperature Preference: From Molecules to Neuronal Circuits in Drosophila.

Temperature has a significant effect on all physiological processes of animals. Suitable temperatures promote responsiveness, movement, metabolism, growth, and reproduction in animals, whereas extreme temperatures can cause injury or even death. Thus, thermosensation is important for survival in all animals. However, mechanisms regulating thermosensation remain unexplored, mostly because of the complexity of mammalian neural circuits. The fruit fly Drosophila melanogaster achieves a desirable body temperature through ambient temperature fluctuations, sunlight exposure, and behavioral strategies. The availability of extensive genetic tools and resources for studying Drosophila have enabled scientists to unravel the mechanisms underlying their temperature preference. Over the past 20 years, Drosophila has become an ideal model for studying temperature-related genes and circuits. This review provides a comprehensive overview of our current understanding of thermosensation and temperature preference in Drosophila. It encompasses various aspects, such as the mechanisms by which flies sense temperature, the effects of internal and external factors on temperature preference, and the adaptive strategies employed by flies in extreme-temperature environments. Understanding the regulating mechanisms of thermosensation and temperature preference in Drosophila can provide fundamental insights into the underlying molecular and neural mechanisms that control body temperature and temperature-related behavioral changes in other animals.

Independent insulin signaling modulators govern hot avoidance under different feeding states.

Thermosensation is critical for the survival of animals. However, mechanisms through which nutritional status modulates thermosensation remain unclear. Herein, we showed that hungry Drosophila exhibit a strong hot avoidance behavior (HAB) compared to food-sated flies. We identified that hot stimulus increases the activity of α'ß' mushroom body neurons (MBns), with weak activity in the sated state and strong activity in the hungry state. Furthermore, we showed that α'ß' MBn receives the same level of hot input from the mALT projection neurons via cholinergic transmission in sated and hungry states. Differences in α'ß' MBn activity between food-sated and hungry flies following heat stimuli are regulated by distinct Drosophila insulin-like peptides (Dilps). Dilp2 is secreted by insulin-producing cells (IPCs) and regulates HAB during satiety, whereas Dilp6 is secreted by the fat body and regulates HAB during the hungry state. We observed that Dilp2 induces PI3K/AKT signaling, whereas Dilp6 induces Ras/ERK signaling in α'ß' MBn to regulate HAB in different feeding conditions. Finally, we showed that the 2 α'ß'-related MB output neurons (MBONs), MBON-α'3 and MBON-ß'1, are necessary for the output of integrated hot avoidance information from α'ß' MBn. Our results demonstrate the presence of dual insulin modulation pathways in α'ß' MBn, which are important for suitable behavioral responses in Drosophila during thermoregulation under different feeding states.

Treatment of Mammary Paget Disease: A systematic review and meta-analysis of real-world data.

BACKGROUND: Because the lesions of mammary Paget disease (MPD) are often limited to the nipple-areolar complex, the extension of optimal tumor excision is inconclusive. Moreover, the risk of potential tumor upstaging is unknown; therefore, the application of sentinel lymph node biopsy (SLNB) is required for analysis. We systematically reviewed the real-world data to evaluate the optimal treatment and potential predictors of poorer prognosis for MPD. METHODS: The PubMed, Embase, and Cochrane Library databases were searched for relevant studies. Clinical studies were included if they evaluated the outcome of positive rates of SLNB, prognostic risk factors of MPD, and survival outcomes of treatments of interest for MPD, including mastectomy, breast-conserving surgery (BCS) with radiotherapy, and BCS alone. RESULTS: A total of 38 studies with 24,062 patients were retrieved. Compared with BCS alone (21.2%), mastectomy (5.9%; P < 0.001) and BCS with radiotherapy (8; P = 0.001) had significantly lower local recurrence rates. Patients with palpable tumors (30.2%) had significantly worse prognoses than those with impalpable (3.4%) tumors in metastasis (P < 0.001), and significantly higher local recurrence rates were observed in patients with underlying invasive carcinoma (6.7%) than those with noninvasive carcinoma (4.5%; P = 0.032). The positive rate of SLNB was 17% (95% CI: 0.115-0.226). CONCLUSION: Except for MPD alone, BCS alone is not recommended for treating MPD with invasive ductal carcinoma and MPD with ductal carcinoma in situ. Moreover, a palpable mass, underlying invasive carcinoma, and positive lymph node status may lead to a poorer prognosis, which may be taken into consideration for the application of SLNB.

Drosophila Model for Studying Gut Microbiota in Behaviors and Neurodegenerative Diseases.

Mounting evidence indicates that the gut microbiota is linked to several physiological processes and disease development in mammals; however, the underlying mechanisms remained unexplored mostly due to the complexity of the mammalian gut microbiome. The fruit fly, Drosophila melanogaster, is a valuable animal model for studying host-gut microbiota interactions in translational aspects. The availability of powerful genetic tools and resources in Drosophila allowed the scientists to unravel the mechanisms by which the gut microbes affect fitness, health, and behavior of their hosts. Drosophila models have been extensively used not only to study animal behaviors (i.e., courtship, aggression, sleep, and learning & memory), but also some human related neurodegenerative diseases (i.e., Alzheimer's disease and Parkinson's disease) in the past. This review comprehensively summarizes the current understanding of the gut microbiota of Drosophila and its impact on fly behavior, physiology, and neurodegenerative diseases.

Serotonin Signals Modulate Mushroom Body Output Neurons for Sustaining Water-Reward Long-Term Memory in Drosophila.

Memory consolidation is a time-dependent process through which an unstable learned experience is transformed into a stable long-term memory; however, the circuit and molecular mechanisms underlying this process are poorly understood. The Drosophila mushroom body (MB) is a huge brain neuropil that plays a crucial role in olfactory memory. The MB neurons can be generally classified into three subsets: γ, αß, and α'ß'. Here, we report that water-reward long-term memory (wLTM) consolidation requires activity from α'ß'-related mushroom body output neurons (MBONs) in a specific time window. wLTM consolidation requires neurotransmission in MBON-γ3ß'1 during the 0-2 h period after training, and neurotransmission in MBON-α'2 is required during the 2-4 h period after training. Moreover, neurotransmission in MBON-α'1α'3 is required during the 0-4 h period after training. Intriguingly, blocking neurotransmission during consolidation or inhibiting serotonin biosynthesis in serotoninergic dorsal paired medial (DPM) neurons also disrupted the wLTM, suggesting that wLTM consolidation requires serotonin signals from DPM neurons. The GFP Reconstitution Across Synaptic Partners (GRASP) data showed the connectivity between DPM neurons and MBON-γ3ß'1, MBON-α'2, and MBON-α'1α'3, and RNAi-mediated silencing of serotonin receptors in MBON-γ3ß'1, MBON-α'2, or MBON-α'1α'3 disrupted wLTM. Taken together, our results suggest that serotonin released from DPM neurons modulates neuronal activity in MBON-γ3ß'1, MBON-α'2, and MBON-α'1α'3 at specific time windows, which is critical for the consolidation of wLTM in Drosophila.

Helicobacter pylori cholesterol-α-glucosyltransferase manipulates cholesterol for bacterial adherence to gastric epithelial cells.

Helicobacter pylori infection is associated with several gastrointestinal diseases, including gastritis, peptic ulcers, and gastric cancer. Infection of cells with H. pylori is dependent on lipid rafts, which are cholesterol-rich microdomains located in the cell membrane. H. pylori cholesterol-α-glucosyltransferase (CGT) catalyzes the conversion of membrane cholesterol to cholesteryl glucosides, which can be incorporated into the bacterial cell wall, facilitating evasion from immune defense and colonization in the host. However, the detailed mechanisms underlying this process remain to be explored. In this study, we discovered for the first time that H. pylori CGT could promote adherence to gastric epithelial cells in a cholesterol-dependent manner. Externalization of cell membrane phosphatidylserine (PS) is crucial for enhancement of binding of H. pylori to cells by CGT and for cytotoxin-associated gene A (CagA)-induced pathogenesis. Furthermore, exogenous cholesterol interferes with the actions of H. pylori CGT to catalyze cellular cholesterol, which impedes bacterial binding to cells and attenuates subsequent inflammation, indicating that the initial attachment of H. pylori to cells is closely dependent on host cholesterol. These results provide evidence that CGT contributes to H. pylori infectivity and it may serve as a key target for the treatment of H. pylori-associated diseases.

Comparison of surgical outcomes for laparoscopic liver resection of large hepatocellular carcinomas: A retrospective observation from single-center experience.

BACKGROUND/PURPOSE: Although laparoscopic liver resection (LLR) is a common surgical procedure for hepatocellular carcinoma (HCC), its suitability for large HCCs (≥5 cm) remains controversial. This study compared surgical outcomes of open hepatectomy with LLR for large HCCs. METHODS: A total of 313 patients with HCC who underwent hepatectomy between January 2010 and June 2017 were analyzed retrospectively. Demographic data, short-term outcomes, and long-term survivals were analyzed. RESULTS: Among patients with large HCCs (n = 122), the open group (n = 85) had larger tumor sizes (10.91 ± 4.72 vs. 7.45 ± 2.95 cm; p < 0.001) and more advanced stages (stages 3/4: 71.8% vs. 45.9%; p = 0.029) than the LLR group (n = 37), while LLR group achieved less blood loss (623.24 ± 841.75 mL vs. 1091.76 ± 1004.72 mL, p = 0.014) and shorter LOS (9.00 ± 5.13 d vs. 12.82 ± 8.51 d, p = 0.013). There were no significant differences in complication and mortality rates between groups. The 5-year overall and recurrence-free survival rates between the two groups were not significantly different (p = 0.408 and 0.644 respectively). The surgical outcomes showed equal benefit of the two operation types. CONCLUSION: With sufficient surgeon experience and appropriate patient selection, LLR is a feasible treatment choice for large HCCs.

Mushroom body subsets encode CREB2-dependent water-reward long-term memory in Drosophila.

Long-term memory (LTM) formation depends on the conversed cAMP response element-binding protein (CREB)-dependent gene transcription followed by de novo protein synthesis. Thirsty fruit flies can be trained to associate an odor with water reward to form water-reward LTM (wLTM), which can last for over 24 hours without a significant decline. The role of de novo protein synthesis and CREB-regulated gene expression changes in neural circuits that contribute to wLTM remains unclear. Here, we show that acute inhibition of protein synthesis in the mushroom body (MB) αß or γ neurons during memory formation using a cold-sensitive ribosome-inactivating toxin disrupts wLTM. Furthermore, adult stage-specific expression of dCREB2b in αß or γ neurons also disrupts wLTM. The MB αß and γ neurons can be further classified into five different neuronal subsets including αß core, αß surface, αß posterior, γ main, and γ dorsal. We observed that the neurotransmission from αß surface and γ dorsal neuron subsets is required for wLTM retrieval, whereas the αß core, αß posterior, and γ main are dispensable. Adult stage-specific expression of dCREB2b in αß surface and γ dorsal neurons inhibits wLTM formation. In vivo calcium imaging revealed that αß surface and γ dorsal neurons form wLTM traces with different dynamic properties, and these memory traces are abolished by dCREB2b expression. Our results suggest that a small population of neurons within the MB circuits support long-term storage of water-reward memory in Drosophila.

Electrical synapses between mushroom body neurons are critical for consolidated memory retrieval in Drosophila.

Electrical synapses between neurons, also known as gap junctions, are direct cell membrane channels between adjacent neurons. Gap junctions play a role in the synchronization of neuronal network activity; however, their involvement in cognition has not been well characterized. Three-hour olfactory associative memory in Drosophila has two components: consolidated anesthesia-resistant memory (ARM) and labile anesthesia-sensitive memory (ASM). Here, we show that knockdown of the gap junction gene innexin5 (inx5) in mushroom body (MB) neurons disrupted ARM, while leaving ASM intact. Whole-mount brain immunohistochemistry indicated that INX5 protein was preferentially expressed in the somas, calyxes, and lobes regions of the MB neurons. Adult-stage-specific knockdown of inx5 in αß neurons disrupted ARM, suggesting a specific requirement of INX5 in αß neurons for ARM formation. Hyperpolarization of αß neurons during memory retrieval by expressing an engineered halorhodopsin (eNpHR) also disrupted ARM. Administration of the gap junction blocker carbenoxolone (CBX) reduced the proportion of odor responsive αß neurons to the training odor 3 hours after training. Finally, the α-branch-specific 3-hour ARM-specific memory trace was also diminished with CBX treatment and in inx5 knockdown flies. Altogether, our results suggest INX5 gap junction channels in αß neurons for ARM retrieval and also provide a more detailed neuronal mechanism for consolidated memory in Drosophila.

Mushroom body glycolysis is required for olfactory memory in Drosophila.

Glucose catabolism, also known as glycolysis, is important for energy generation and involves a sequence of enzymatic reactions that convert a glucose molecule into two pyruvate molecules. The glycolysis process generates adenosine triphosphate as a byproduct. In this study, we investigated whether glycolysis plays a role in maintaining neuronal functions in the Drosophila mushroom bodies (MBs), which are generally accepted to be an olfactory learning and memory center. Our data showed that individual knockdown of glycolytic enzymes in the MBs, including hexokinase (HexA), phosphofructokinase (Pfk), or pyruvate kinase (PyK), disrupts olfactory memory. Whole-mount brain immunostaining indicated that pyruvate kinase is strongly expressed in the MB αß, α'ß', and γ neuron subsets. We conclude that HexA, Pfk, and PyK are required in each MB neuron subset for olfactory memory formation. Our data therefore indicates that glucose catabolism in the MBs is important for olfactory memory formation in Drosophila.

Neural circuits for long-term water-reward memory processing in thirsty Drosophila.

The intake of water is important for the survival of all animals and drinking water can be used as a reward in thirsty animals. Here we found that thirsty Drosophila melanogaster can associate drinking water with an odour to form a protein-synthesis-dependent water-reward long-term memory (LTM). Furthermore, we found that the reinforcement of LTM requires water-responsive dopaminergic neurons projecting to the restricted region of mushroom body (MB) ß' lobe, which are different from the neurons required for the reinforcement of learning and short-term memory (STM). Synaptic output from α'ß' neurons is required for consolidation, whereas the output from γ and αß neurons is required for the retrieval of LTM. Finally, two types of MB efferent neurons retrieve LTM from γ and αß neurons by releasing glutamate and acetylcholine, respectively. Our results therefore cast light on the cellular and molecular mechanisms responsible for processing water-reward LTM in Drosophila.

Additive Expression of Consolidated Memory through Drosophila Mushroom Body Subsets.

Associative olfactory memory in Drosophila has two components called labile anesthesia-sensitive memory and consolidated anesthesia-resistant memory (ARM). Mushroom body (MB) is a brain region critical for the olfactory memory and comprised of 2000 neurons that can be classified into αß, α'ß', and γ neurons. Previously we demonstrated that two parallel pathways mediated ARM consolidation: the serotonergic dorsal paired medial (DPM)-αß neurons and the octopaminergic anterior paired lateral (APL)-α'ß' neurons. This finding prompted us to ask how this composite ARM is retrieved. Here, we showed that blocking the output of αß neurons and that of α'ß' neurons each impaired ARM retrieval, and blocking both simultaneously had an additive effect. Knockdown of radish and octß2R in αß and α'ß' neurons, respectively, impaired ARM. A combinatorial assay of radish mutant background rsh1 and neurotransmission blockade confirmed that ARM retrieved from α'ß' neuron output is independent of radish. We identified MBON-ß2ß'2a and MBON-ß'2mp as the MB output neurons downstream of αß and α'ß' neurons, respectively, whose glutamatergic transmissions also additively contribute to ARM retrieval. Finally, we showed that α'ß' neurons could be functionally subdivided into α'ß'm neurons required for ARM retrieval, and α'ß'ap neurons required for ARM consolidation. Our work demonstrated that two parallel neural pathways mediating ARM consolidation in Drosophila MB additively contribute to ARM expression during retrieval.

Magnetoreception Regulates Male Courtship Activity in Drosophila.

The possible neurological and biophysical effects of magnetic fields on animals is an area of active study. Here, we report that courtship activity of male Drosophila increases in a magnetic field and that this effect is regulated by the blue light-dependent photoreceptor cryptochrome (CRY). Naïve male flies exhibited significantly increased courtship activities when they were exposed to a ≥ 20-Gauss static magnetic field, compared with their behavior in the natural environment (0 Gauss). CRY-deficient flies, cryb and crym, did not show an increased courtship index in a magnetic field. RNAi-mediated knockdown of cry in cry-GAL4-positive neurons disrupted the increased male courtship activity in a magnetic field. Genetically expressing cry under the control of cry-GAL4 in the CRY-deficient flies restored the increase in male courtship index that occurred in a magnetic field. Interestingly, artificially activating cry-GAL4-expressing neurons, which include large ventral lateral neurons and small ventral lateral neurons, via expression of thermosensitive cation channel dTrpA1, also increased the male courtship index. This enhancement was abolished by the addition of the cry-GAL80 transgene. Our results highlight the phenomenon of increased male courtship activity caused by a magnetic field through CRY-dependent magnetic sensation in CRY expression neurons in Drosophila.

Determination the active compounds of herbal preparation by UHPLC-MS/MS and its application on the preclinical pharmacokinetics of pure ephedrine, single herbal extract of Ephedra, and a multiple herbal preparation in rats.

The herbal preparation Ma-Xing-Gan-Shi-Tang (MXGST) is a popular traditional Chinese formulation that has been used for the treatment of coughs and fevers. The potential active components of MXGST are ephedrine, amygdalin, and glycyrrhizic acid. The aim of this study was to develop a validated analytical method to measure these analytes in the herbal preparation MXGST using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Multiple reaction monitoring (MRM) was used to monitor m/z 166.1→148.1 for ephedrine ([M+H](+)), 475.2→163.0 for amygdalin ([M+NH4](+)), and 840.6→453.3 ([M+NH4](+)) for glycyrrhizic acid. The analytes were separated by a reverse phase C18 column (100×2.1mm, 2.6µm). The mobile phase consisted of 5mM ammonium acetate (0.1% formic acid) and 100% methanol (0.1% formic acid) with a linear gradient elution. Five brands of commercial pharmaceutical herbal products and a laboratory extract of MXGST were analyzed. Moreover, the modified UHPLC-MS/MS method was applied to the comparative pharmacokinetics of ephedrine in rats from the following three sources: (1) pure ephedrine, (2) an herbal extract of Ephedra, and (3) an herbal preparation of MXGST. Plasma samples from rats were prepared by protein precipitation, evaporation and reconstitution. The pharmacokinetic data showed that pure ephedrine was absorbed significantly faster than ephedrine of the Ephedra extract or the MXGST herbal preparation. However, the elimination half-life of ephedrine administered as the pure compound was 93.9±8.07min, but for ephedrine from the Ephedra extract and the MXGST, the half-lives were 133±17 and 247±57.6min, respectively. The area under the concentration curves (AUC) did not show significant differences among the three groups. These data suggest that the rest of the herbal ingredients in the Ephedra extract and the MXGST may provide a compensation effect that reduces the peak concentration of ephedrine and prolongs the elimination half-life.

Herb-drug pharmacokinetic interaction of a traditional chinese medicine jia-wei-xiao-yao-san with 5-Fluorouracil in the blood and brain of rat using microdialysis.

According to a survey from the National Health Insurance Research Database (NHIRD), Jia-Wei-Xiao-Yao-San (JWXYS) is the most popular Chinese medicine for cancer patients in Taiwan. 5-Fluorouracil (5-FU) is a general anticancer drug for the chemotherapy. To investigate the herb-drug interaction of JWXYS on pharmacokinetics of 5-FU, a microdialysis technique coupled with a high-performance liquid chromatography system was used to monitor 5-FU in rat blood and brain. Rats were divided into four parallel groups, one of which was treated with 5-FU (100 mg/kg, i.v.) alone and the remaining three groups were pretreated with a different dose of JWXYS (600, 1200, or 2400 mg/kg/day for 5 consecutive days) followed by a combination with 5-FU. This study demonstrates that 5-FU with JWXYS (600 mg/kg/day or 1200 mg/kg/day) has no significant effect on the pharmacokinetics of 5-FU in the blood and brain. However, JWXYS (2400 mg/kg/day) coadministered with 5-FU extends the elimination half-life and increases the volume of distribution of 5-FU in the blood. The elimination half-life of 5-FU in the brain for the pretreatment group with 2400 mg/kg/day of JWXYS is significantly longer than that for the group treated with 5-FU alone and also reduces the clearance. This study provides practical dosage information for clinical practice and proves the safety of 5-FU coadministered with JWXYS.

Head and neck irradiation modulates pharmacokinetics of 5-fluorouracil and cisplatin.

BACKGROUND: 5-fluorouracil (5-FU) and cisplatin (CDDP) are used to enhance radiotherapy (RT) effect for head and neck (HN) cancers. However, the effect of local RT on systemic chemotherapeutics remains unclear. Here, we evaluated the influence of HN irradiation on the pharmacokinetics (PK) of 5-FU and CDDP in rats as experimental model. METHODS: The radiation dose distributions of HN cancer patients were determined for the low dose areas, which are generously deposited around the target volume. Two Gy and 0.5 Gy RT were selected. Single-fraction radiation was delivered to the HN of Sprague-Dawley rats. 5-FU at 100 mg/kg or CDDP at 5 mg/kg was intravenously infused 24 hours after radiation. RESULTS: Radiation at 2 Gy reduced the area under the plasma concentration vs. time curve (AUC) of 5-FU and CDDP by 16% and 29% compared to non-irradiated controls, respectively. This was accompanied by incremental total plasma clearance values. Intriguingly, low dose radiation at 0.5 Gy resulted in a similar pharmacokinetic profile, with a 17% and 33% reduction in the AUC of 5-FU and CDDP, respectively. The changes in AUC of bile, which increases with RT, were opposite to AUC of plasma for both drugs. CONCLUSIONS: The local HN RT could modulate systemic PK of 5-FU and CDDP in rats. This unexpected RT-PK phenomena may provide a reference for adjustment of drug administration and is worthy of further investigation. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT01755585 and NCT01609114.