Prediction of evapotranspiration variance in the Budyko framework with the incorporation of soil storage and runoff.

Water availability needs to be accurately assessed to understand and effectively manage hydrologic environments. However, the estimation of evapotranspiration (ET) is prone to errors due to the complex interactions that occur between the atmosphere, the Earth's surface, and vegetation cover. This paper proposes a novel approach for analyzing the sources of inaccuracy in estimating the annual ET using the Budyko framework (BF), particularly temporal variability in precipitation (P), potential evapotranspiration (EP), runoff (R), and the change in soil storage (ΔS). Error decomposition is employed to determine the individual contributions of P, R, EP, and ΔS to the ET error variance at 12 locations in the state of Illinois using a dataset covering a 22-year period. To the best of our knowledge, this study represents the first BF-based investigation that considers R in the error decomposition of the predicted ET variance. The ET error variance increases with the variance in the P and R in Illinois and decreases with the covariance between these two variables. In addition, when accounting for ΔS in the BF, the scenario in which ΔS affects the total available water (i.e., P) is reliable, with a low prediction error and a 13.87 % lower root mean square error compared with the scenario in which the effect of ΔS is negligible. We thus recommend the inclusion of ΔS and R as key variables in the BF to improve water budget estimations.

Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity.

Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT-NAD+-CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity.

Characterization of lymphocyte-rich hepatocellular carcinoma and the prognostic role of tertiary lymphoid structures.

BACKGROUND & AIMS: Lymphocyte-rich hepatocellular carcinoma (LR-HCC) is largely unknown and a rare subtype of HCC with immune-rich stroma. Tertiary lymphoid structures (TLS), frequently observed in LR-HCC, are known to be prognostically significant in various malignancies; however, their significance in HCC remains unevaluated. METHODS: Clinicopathologic data of 191 cases of surgically resected conventional HCC (C-HCC, n = 160) and LR-HCC (n = 31) were retrieved. Immunohistochemistry, multiplex immunofluorescence staining, RNA sequencing and proteomic analysis were conducted. Differences between the subtypes were statistically evaluated. RESULTS: LR-HCC was significantly correlated to larger tumour size, higher Edmondson-Steiner grade, presence of TLS and higher CD3-, CD8- and FOXP3-positive T cell, high PD-1 and PD-L1 expression (p < .001 for all) compared to C-HCC. Patients with LR-HCC exhibited significantly better overall survival (OS) (p = .044) and recurrence-free survival (RFS) (p = .025) than C-HCC. LR-HCC demonstrated TLS signatures with significantly higher proteomic-based immune scores in 14 of 17 types of tumour-infiltrating immune cells. Furthermore, C-HCC with secondary follicles, the most mature form of TLS, exhibited significantly better OS (p = .031) and RFS (p = .033) than those without. Across the global proteome, LR-HCC was well-differentiated from C-HCC and a map of protein-protein interactions between tumour-infiltrating lymphocytes and HCC in tumour microenvironment was completed. CONCLUSION: LR-HCC is clinicopathologically and molecularly distinct and shows better prognosis compared to C-HCC. Also, the presence of secondary follicle can be an important prognostic marker for better prognosis in both LR-HCC and C-HCC.

PD-1-positive cells contribute to the diagnosis of inflammatory bowel disease and can aid in predicting response to vedolizumab.

Differentiating inflammatory bowel disease (IBD) from other inflammatory diseases is often challenging. Programmed cell death protein-1 (PD-1) is expressed in T cells and is an indicator of their exhaustion. The role of PD-1 expression in diagnosing IBD and predicting the response of biologic agents remains inconclusive. In this study, endoscopic biopsy samples of 19 patients diagnosed with IBD, intestinal tuberculosis, and intestinal Behcet's disease were analyzed using multiplexed immunohistochemistry. Additionally, a separate "vedolizumab (VDZ) cohort" established in ulcerative colitis patients who underwent endoscopic biopsy before VDZ administration was analyzed to predict response to VDZ. In the immunohistochemistry analysis, the cell density of T cell subsets, including PD-1 + cells, was investigated and compared between IBD and other inflammatory diseases (OID). Cell densities of PD-1 + cells (p = 0.028), PD-1 + helper T cells (p = 0.008), and PD-1 + regulatory T cells (p = 0.024) were higher in IBD compared with OID. In the VDZ cohort, patients with a 14-week steroid-free clinical response had higher levels of PD-1 + cells (p = 0.026), PD-1 + helper T cells (p = 0.026), and PD-1 + regulatory T cells (p = 0.041) than the no response group. PD-1 + immune cells may contribute to the diagnosis of IBD and could be used to predict response to VDZ in ulcerative colitis patients.

Clinical Outcomes of Small Cell Carcinoma of the Genitourinary Tract and the Prognostic Significance of the Tumor Immune Microenvironment.

Purpose: Small cell carcinoma of the genitourinary tract (GU SCC) is a rare disease with a poor prognosis. There are only limited treatment options due to insufficient understanding of the disease. In this study, we analyzed the clinical outcomes of patients with GU SCC and their association with the tumor immune phenotype. Materials and Methods: Patients diagnosed with GU SCC were included. Survival outcomes according to the primary location (prostate and non-prostate) and stages (limited disease [LD] and extensive disease [ED]) were analyzed. We performed multiplex immunohistochemistry (IHC) in non-prostate SCC patients and analyzed the immune cell population. Results: A total of 77 patients were included in this study. Their median age was 71 years, 67 patients (87.0%) were male, and 48 patients (62.3%) had non-prostate SCC. All patients with ED (n=31, 40.3%) received etoposide plus platinum (EP) as initial treatment and median overall survival (OS) was 9.7 months (95% CI 7.1-18.6 months). Patients with LD (n=46, 59.7%) received EP followed by radiotherapy or surgery, and 24-months OS rate was 63.6% (95% CI 49.9-81.0). The multiplex IHC analysis of 21 patients with non-prostate SCC showed that patients with a higher density of PD-L1-expressing CD68+CD206+ M2-like macrophages had significantly worse OS outcomes with an adjusted hazards ratio of 4.17 (95% CI 1.25-14.29, adjusted p=0.02). Conclusion: Patients with GU SCC had a poor prognosis, even those with localized disease. The tumor immune phenotypes were significantly associated with survival. This finding provides new insights for treating GU SCC.

Cyclosporin A inhibits prostate cancer growth through suppression of E2F8 transcription factor in a MELK­dependent manner.

The treatment of advanced prostate cancer remains a formidable challenge due to the limited availability of effective treatment options. Therefore, it is imperative to identify promising druggable targets that provide substantial clinical benefits and to develop effective treatment strategies to overcome therapeutic resistance. Cyclosporin A (CsA) showed an anticancer effect on prostate cancer in cultured cell and xenograft models. E2F8 was identified as a master transcription factor that regulated a clinically significant CsA specific gene signature. The expression of E2F8 increased during prostate cancer progression and high levels of E2F8 expression are associated with a poor prognosis in patients with prostate cancer. MELK was identified as a crucial upstream regulator of E2F8 expression through the transcriptional regulatory network and Bayesian network analyses. Knockdown of E2F8 or MELK inhibited cell growth and colony formation in prostate cancer cells. High expression levels of E2F8 and androgen receptor (AR) are associated with a worse prognosis in patients with prostate cancer compared with low levels of both genes. The inhibition of E2F8 improved the response to AR blockade therapy. These results suggested that CsA has potential as an effective anticancer treatment for prostate cancer, while also revealing the oncogenic role of E2F8 and its association with clinical outcomes in prostate cancer. These results provided valuable insight into the development of therapeutic and diagnostic approaches for prostate cancer.

Integrating biological ion exchange with biological activated carbon treatment for drinking water: A novel approach for NOM removal, trihalomethane formation potential, and biological stability.

Ion exchange resins (IEX) are used in drinking water utilities to remove natural organic matter (NOM) from surface water; however, the disposal of used brine can be a major drawback. Recently, biological ion exchange (BIEX) has been proposed as an alternative to biological activated carbon (BAC) for removing natural organic matter (NOM). The present study is, to the best of our knowledge, the first attempt to use a hybrid BIEX and BAC (BIEX+BAC) system for drinking water treatment. The removal of NOM, assimilable organic carbon, and trihalomethane formation potential was investigated by operating four columns comprising IEX, BIEX, BAC, and BIEX+BAC with 18,000 bed volumes. The BIEX+BAC system was the most effective at removing dissolved organic carbon (59.9%). Based on fluorescence excitation-emission matrix spectroscopy, the BIEX+BAC column showed the maximum removal rates in all peak regions of T1, T2, and A. Using liquid chromatography-organic carbon detection, resin-containing columns were found to effectively remove humic substances, which are the principal precursors of trihalomethanes. The lowest potential for trihalomethane formation was observed in BIEX+BAC. BIEX+BAC also had the highest assimilable organic carbon removal efficiency (61.2%) followed by BIEX (52.3%), BAC (49.5%), and IEX (47.1%). The BIEX+BAC hybrid was found to be the most effective method for removing NOM fractions and reducing the formation of disinfection byproducts.

Clinical Usefulness of Immune Profiling for Differential Diagnosis between Crohn's Disease, Intestinal Tuberculosis, and Behcet's Disease.

It is important to make a differential diagnosis between inflammatory diseases of the bowel with similar clinical and endoscopic features. The profiling of immune cells could be helpful for accurately diagnosing inflammatory bowel diseases. We compared immune marker expression between Crohn's disease (CD), intestinal Behcet's disease (BD), and intestinal tuberculosis (TB) and evaluated the usefulness of immune profiling in differentiating between these diseases. Biopsy specimens were acquired around ulcerations on the terminal ileum or cecum from five patients with each disease. Panel 1 included multiplex immunohistochemistry staining for CD8, CD4, Foxp3, CD20, programmed death-1, and granzyme B. CD56, CD68, CD163, CD11c, and HLA-DR were analyzed in panel 2. The differences in cytotoxic T cells (CD8+CD4-Fopx3-CD20-), helper T cells (CD8-CD4+Fopx3-CD20-), and regulatory T cells (CD8-CD4+Fopx3+CD20-) were also not significant. However, M1 macrophage (CD68+CD163-HLA-DR-) cell densities were significantly higher in intestinal BD than in other diseases. The expression level of dendritic cells (CD56-CD68-CD163-CD11c+HLA-DR+) was highest in intestinal TB and lowest in intestinal BD. The expression of immune cells, including M1 macrophages and dendritic cells, was different between CD, intestinal BD, and intestinal TB. Immune profiling can be helpful for establishing differential diagnoses of inflammatory bowel diseases.

Effects of the purified dry extract of fermented ginseng BST204 on muscle fiber regeneration.

Background: Sarcopenia and muscular dystrophy are two muscle diseases. In cancer patients, cancer cachexia induces continuous weight loss and muscle loss due to the disease itself or the use of anticancer drugs. Cachexia occurs in up to 80% of cancer patients. It is recognized as a direct cause of reduced quality of life, contributing to at least 20% of cancer-associated deaths and limiting therapeutic options for cancer patients. Cancer cachexia is associated with multiple chronic or end-stage conditions and develops similarly. There are various options for the treatment of cancer cachexia, but there are still many issues to be solved. Hence, to determine its potential to overcome the muscle wasting during cancer cachexia, we studied the effect of BST204, a refined dry ginseng extract, on muscle fiber regeneration. Experimental procedure: We checked the muscle regeneration efficacy of BST204. First, BaCl2 and freeze injury models were selected to investigate muscle regeneration after BST204 administration. In addition, after inducing muscle differentiation of C2C12 cells, the efficacy of BST204 was analyzed. In this model, we analyzed the expression of the signal pathway (PI3K-AKT signal) by Western blot and imaging methods. Results and conclusion: These results showed that BST204 induced muscle fiber regeneration in BaCl2 and freeze injury models. Also, we confirmed that BST204 could regulate the PI3K/AKT signaling pathway and regulate the differentiation of C2C12 cells. These results indicate that BST204 has the potential to facilitate the skeletal muscle regeneration during muscle wasting induced by various factors including cancer cachexia.

Effects of a sidestream concentrated oxygen supply system on the membrane filtration performance of a high-loaded membrane bioreactor.

To investigate the influence of high-pressure and shear effects introduced by a concentrated oxygen supply system on the membrane filtration performance, a laboratory-scale membrane bioreactor (MBR) fed artificial municipal wastewater was operated continuously for 80 days in four phases equipped with different aerations systems: (P1) bubble diffusers (days 0-40), (P2) concentrated oxygen supply system, the supersaturated dissolved oxygen (SDOX) (days 41-56), (P3) bubble diffusers (days 57-74), and (P4) SDOX (days 75-80). Various sludge physical-chemical parameters, visual inspection of the membrane, and permeability evaluations were performed. Results showed that the high-pressure effects contributed to fouling of the membranes compared to the bubble diffuser aeration system. Biofouling by microorganisms appeared to be the main contributor to the cake layer when bubble diffusers were used, while fouling by organic matter seemed to be the main contributor to the cake layer when SDOX was used. Small particle size distribution (PSD) (ranging from 1 to 10 and 1-50 µm in size) fractions are a main parameter affecting the intense fouling of membranes (e.g., formation of a dense and thin cake layer). However, PSD alone cannot explain the worsened membrane fouling tendency. Therefore, it can be assumed that a combination of several factors (which certainly includes PSD) led to the severe membrane fouling caused by the high-pressure and shear.

Changes in peripheral blood immune cell population in thyroid cancer patients treated with lenvatinib.

This study evaluated changes in the peripheral blood immune cell population in patients with advanced thyroid cancer receiving lenvatinib treatment to confirm the immune-modulatory effect of lenvatinib. After obtaining informed consent from patients, we prospectively collected 20 ml of whole blood at 2-3 months intervals 2-4 times from each patient; peripheral blood mononuclear cells (PBMCs) were separated, and the Maxpar Direct Immune Profiling Assay was performed. A total of 10 patients were enrolled, and 31 blood samples were obtained. The median age of patients was 65 years, and all patients showed durable responses to the lenvatinib treatment. When we compared the PBMC profiles between the pre-treatment, on-treatment, and off-treatment samples, the peripheral natural killer (NK) cell proportion differed significantly. The proportion of NK cells among total live cells significantly increased from 9.3 ± 4.5 (%) in the pre-treatment samples to 20.8 ± 7.9 (%) in the on-treatment samples (P = 0.009) and decreased to 13.3 ± 3.1 (%) in the off-treatment samples (P = 0.07). There was a significant increase in the peripheral NK cell population with lenvatinib treatment in advanced thyroid cancer patients. This finding confirms the immune-modulatory effect of lenvatinib.

Biomass formation and organic carbon migration potential of microplastics from a PET recycling plant: Implication of biostability.

The growth of the polyethylene terephthalate (PET) mechanical recycling industry has resulted in the challenge of generating microplastics (MPs). However, little attention has been given to investigating the release of organic carbon from these MPs and their roles in promoting bacterial growth in aquatic environments. In this study, a comprehensive method is proposed to access the potential of organic carbon migration and biomass formation of MPs generated from a PET recycling plant, and to understand its impact on the biological systems of freshwater habitats. Various MPs sizes from a PET recycling plant were selected to conduct a series of tests, including the organic carbon migration test, biomass formation potential test, and microbial community analysis. The MPs smaller than 100 µm, which are difficult to remove from the wastewater, exhibited greater biomass in the observed samples (1.05 × 1011 bacteria per gram MPs). Moreover, PET MPs altered the microbial diversity, with Burkholderiaceae becoming the most abundant, while Rhodobacteraceae was eliminated after being incubated with MPs. This study partly revealed that organic matter adsorbed on the surface of MPs was a significant nutrient source that increased biomass formation. PET MPs acted not only as carriers for microorganisms but also for organic matter. As a result, it is crucial to develop and refine recycling methods in order to decrease the production of PET MPs and minimize their adverse effects on the environment.

Serum proteins for monitoring and predicting visual function in patients with recent optic neuritis.

It is unclear whether serum proteins can serve as biomarkers to reflect pathological changes and predict recovery in inflammation of optic nerve. We evaluated whether serum proteins could monitor and prognosticate optic neuritis (ON). We prospectively recruited consecutive patients with recent ON, classified as ON with anti-aquaporin-4 antibody (AQP4-ON), ON with anti-myelin oligodendrocyte glycoprotein antibody (MOG-ON), and double-seronegative ON (DSN-ON). Using ultrasensitive single-molecule array assays, we measured serum neurofilament light chain and glial fibrillary acidic protein (GFAP), and brain-derived neurotrophic factor (BDNF). We analyzed the markers according to disease group, state, severity, and prognosis. We enrolled 60 patients with recent ON (15 AQP4-ON; 14 MOG-ON; 31 DSN-ON). At baseline, AQP4-ON group had significantly higher serum GFAP levels than did other groups. In AQP4-ON group, serum GFAP levels were significantly higher in the attack state than in the remission state and correlated with poor visual acuity. As a prognostic indicator, serum BDNF levels were positively correlated with follow-up visual function in the AQP4-ON group (r = 0.726, p = 0.027). Serum GFAP reflected disease status and severity, while serum BDNF was identified as a prognostic biomarker in AQP4-ON. Serum biomarkers are potentially helpful for patients with ON, particularly those with AQP4-ON.

Disease characteristics of idiopathic transverse myelitis with serum neuronal and astroglial damage biomarkers.

Despite its close association with CNS inflammatory demyelinating disorders (CIDDs), pathogenic characteristics of idiopathic transverse myelitis (ITM) remain largely unknown. Here, we investigated serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) in patients with ITM to unravel the disease characteristics of ITM. We prospectively recruited 70 patients with ITM, 62 with AQP4 + NMOSD and 85 with RRMS-including 31 patients with acute TM attacks-along with 30 HCs. We measured sNfL and sGFAP levels using single-molecular arrays and compared these levels per lesion volume between the disease groups during attacks. Compared to HCs, ITM patients showed higher sNfL and sGFAP during acute attacks (sNfL: p < 0.001, sGFAP: p = 0.024), while those in remission (sNfL: p = 0.944, sGFAP: p > 0.999) did not, regardless of lesion extents and presence of multiple attacks. ITM patients demonstrated lower sGFAP/volume (p = 0.011) during acute attacks and lower sGFAP (p < 0.001) in remission compared to AQP4 + NMOSD patients. These findings suggest that both neuronal and astroglial damages occur in patients with acute ITM attacks at a similar level to those with RRMS, distinct from AQP4 + NMOSD. However, active neuroinflammatory process was not remarkable during remission in this cohort.

TGFBI remodels adipose metabolism by regulating the Notch-1 signaling pathway.

Extracellular matrix proteins are associated with metabolically healthy adipose tissue and regulate inflammation, fibrosis, angiogenesis, and subsequent metabolic deterioration. In this study, we demonstrated that transforming growth factor-beta (TGFBI), an extracellular matrix (ECM) component, plays an important role in adipose metabolism and browning during high-fat diet-induced obesity. TGFBI KO mice were resistant to adipose tissue hypertrophy, liver steatosis, and insulin resistance. Furthermore, adipose tissue from TGFBI KO mice contained a large population of CD11b+ and CD206+ M2 macrophages, which possibly control adipokine secretion through paracrine mechanisms. Mechanistically, we showed that inhibiting TGFBI-stimulated release of adipsin by Notch-1-dependent signaling resulted in adipocyte browning. TGFBI was physiologically bound to Notch-1 and stimulated its activation in adipocytes. Our findings revealed a novel protective effect of TGFBI deficiency in obesity that is realized via the activation of the Notch-1 signaling pathway.

Epithelial-Mesenchymal Transition Phenotype and Peritumoral Immune Cell Infiltration in Advanced Biliary Tract Cancer.

BACKGROUND/AIM: This study evaluated the clinical implications of epithelial-mesenchymal transition (EMT) markers and peritumoral immune cell infiltration in patients with biliary tract cancer (BTC) treated with gemcitabine plus cisplatin (GemCis). MATERIALS AND METHODS: Forty-five patients with advanced BTC who received GemCis were included as the study population. We conducted multiplex immunohistochemistry and examined EMT markers and their correlations with immune cell infiltrate at the invasive tumor margin. Study population was subdivided into two groups: twenty-four patients with overall survival (OS) less than 10 months (short-term survivor group, SS) and 21 with OS of 20 months or longer (long-term survivor group, LS). RESULTS: The density of tumor cells expressing epithelial marker E-cadherin (E-cadherin+ CK+) at the invasive tumor margin tended to be higher in the LS group than that in the SS group (p=0.065). The density of tumor cells expressing mesenchymal marker vimentin (vimentin+ CK+) was significantly higher in the SS group than that in the LS group (p=0.021). The density of E-cadherin- vimentin+ tumor cells (E-cadherin- vimentin+ CK+) was also significantly higher in the SS group (p=0.020). The density of OX40 expressing cells was significantly higher in the SS group compared to that in the LS group (p=0.006). The density of vimentin-expressing tumor cells was positively correlated with FoxP3+ CD4+ regulatory T-cells (r=0.29, p=0.047) and OX40+ cells (r=0.48, p<0.001). CONCLUSION: EMT-related features were enriched in BTC patients with poor survival outcomes and associated with regulatory T-cell infiltration.

- Invited Review - Factors affecting beef quality and nutrigenomics of intramuscular adipose tissue deposition.

Beef quality is characterized by marbling (marbling degree and marbling fineness), physiochemical (shear force, meat color, fat color, texture, and maturity), and sensory (tenderness, flavor, juiciness, taste, odor, and appearance) traits. This paper summarizes and addresses beef-quality characteristics and the beef-grading systems in Korea, Japan, the USA, and Australia. This paper summarizes recent research progresses on the genetic and nutritional factors that affect beef quality. Intramuscular (i.m.) adipose tissue deposition or marbling is a major determinant of beef quality. This paper addresses the mechanisms of i.m. adipose tissue deposition focused on adipogenesis and lipogenesis. We also address selected signaling pathways associated with i.m. adipose tissue deposition. Nutrients contribute to the cellular response and phenotypes through gene expression and metabolism. This paper addresses control of gene expression through several nutrients (carbohydrates, fat/fatty acids, vitamins, etc.) for i.m. adipose tissue deposition. Several transcription factors responsible for gene expression via nutrients are addressed. We introduce the concept of genome-based precision feeding in Korean cattle.

Comprehensive evaluation of the tumor immune microenvironment and its dynamic changes in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy: From the phase II ADORE study.

A better understanding of the effects of preoperative chemoradiotherapy (CRT) on tumor immune microenvironment (TIME) is essential to improve the treatment outcomes of patients with locally advanced rectal cancer (LARC). In this context, we performed a multiplex immunofluorescence staining to evaluate the TIME in 158 patients with LARC who underwent preoperative CRT followed by surgery and adjuvant chemotherapy in the ADORE trial. We found that higher levels of T-cell subsets (CD3+, CD4+, and CD8+) and dendritic cells in the tumor compartment of pretreatment biopsy samples were associated with good response to preoperative CRT. After CRT, there was a significant increase in the densities of CD3+ T cells, CD8+ T cells, and dendritic cells, while that of CD4+FoxP3+ regulatory T cells decreased, indicating that CRT changed the TIME into a more immune-active status. However, CRT also conferred an immunosuppressive effect by polarizing the tumor-associated macrophages from pro-inflammatory M1 macrophage to immune-suppressive M2 macrophages and decreasing the density of B cells. High delta values of CD3+ T cells and PD-L1+ lymphocytes after CRT were associated with good disease-free survival (DFS), while that of CD4+FoxP3+ regulatory T cells was associated with poor DFS. These findings provide a framework for future studies incorporating strategies to modulate the TIME in patients with LARC.

Duodenal Dual-Wavelength Photobiomodulation Improves Hyperglycemia and Hepatic Parameters with Alteration of Gut Microbiome in Type 2 Diabetes Animal Model.

BACKGROUND: Recently, the duodenum has garnered interest for its role in treating metabolic diseases, including type 2 diabetes (T2DM). Multiple sessions of external photobiomodulation (PBM) in previous animal studies suggested it resulted in improved hyperglycemia, glucose intolerance, and insulin resistance with a multifactorial mechanism of action, despite the target organ of PBM not being clearly proven. This study aimed to determine whether a single session of a duodenal light-emitting diode (LED) PBM may impact the T2DM treatment in an animal model. METHODS: Goto-Kakizaki rats as T2DM models were subjected to PBM through duodenal lumen irradiation, sham procedure, or control in 1-week pilot (630 nm, 850 nm, or 630/850 nm) and 4-week follow-up (630 nm or 630/850 nm) studies. Oral glucose tolerance tests; serum glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide, and insulin levels; liver chemistry and histology; and gut microbiome in the PBM, sham control, and control groups were evaluated. RESULTS: In the 1-week study, duodenal dual-wavelength (D, 630/850 nm) LED PBM showed improved glucose intolerance, alkaline phosphatase and cholesterol levels, and weight gain than other groups. The D-LED PBM group in the 4-week study also showed improved hyperglycemia and liver enzyme levels, with relatively preserved pancreatic islets and increased serum insulin and GLP-1 levels. Five genera (Bacteroides, Escherichia, Parabacteroides, Allobaculum, and Faecalibaculum) were significantly enriched 1 week after the D-LED PBM. Bacteroides acidifaciens significantly increased, while Lachnospiraceae significantly decreased after 1 week. CONCLUSION: A single session of D-LED PBM improved hyperglycemia and hepatic parameters through the change of serum insulin, insulin resistance, insulin expression in the pancreatic ß-cells, and gut microbiome in T2DM animal models.

Clinical implications of the tumor microenvironment using multiplexed immunohistochemistry in patients with advanced or metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

Purpose: Immune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab (N/I) are important treatment options for advanced renal cell carcinoma (RCC). The tumor microenvironment (TME) in these ICI-treated patients is largely unknown. Methods: Twenty-four patients treated with N/I between July 2015 and June 2020 were analyzed. Multiplexed immunohistochemistry (mIHC) was conducted to define the TME, including various T cell subsets, B cells, macrophages, and dendritic cells. Results: The median age of the study patients was 61 years (range, 39-80) and 75.0% of these cases were men. The objective response rate with N/I was 50.0%. The densities of the CD8+ cytotoxic T cells (P=0.005), specifically CD137+ CD8+ T cells (P=0.017), Foxp3- CD4+ helper T cells (P=0.003), Foxp3+ CD4+ regulatory T cells (P=0.045), CD68+ CD206- M1 macrophages (P=0.008), and CD68+ CD206+ M2 macrophages (P=0.021) were significantly higher in the treatment responders. At a median follow-up duration of 24.7 months, the median progression-free survival (PFS) was 11.6 months. The high densities (≥median) of Foxp3- CD4+ helper T cells (P=0.016) and CD68+ CD206- M1 macrophages (P=0.008) were significantly associated with better PFS, and the density of CD137+ CD8+ cytotoxic T cells (P=0.079) was marginally associated with better PFS. After multivariate analysis, the higher density of Foxp3- CD4+ helper T cells was independently associated with better PFS (hazard ratio 0.19; P=0.016). Conclusion: The properties and clinical implications of the TME properties in RCC indicate that Foxp3- CD4+ helper T cells, M1 macrophages, and CD137+ CD8+ T cells are potential predictive biomarkers and treatment targets.