Hepatocytes coordinate immune evasion in cancer via release of serum amyloid A proteins.

T cell infiltration into tumors is a favorable prognostic feature, but most solid tumors lack productive T cell responses. Mechanisms that coordinate T cell exclusion are incompletely understood. Here we identify hepatocyte activation via interleukin-6/STAT3 and secretion of serum amyloid A (SAA) proteins 1 and 2 as important regulators of T cell surveillance of extrahepatic tumors. Loss of STAT3 in hepatocytes or SAA remodeled the tumor microenvironment with infiltration by CD8+ T cells, while interleukin-6 overexpression in hepatocytes and SAA signaling via Toll-like receptor 2 reduced the number of intratumoral dendritic cells and, in doing so, inhibited T cell tumor infiltration. Genetic ablation of SAA enhanced survival after tumor resection in a T cell-dependent manner. Likewise, in individuals with pancreatic ductal adenocarcinoma, long-term survivors after surgery demonstrated lower serum SAA levels than short-term survivors. Taken together, these data define a fundamental link between liver and tumor immunobiology wherein hepatocytes govern productive T cell surveillance in cancer.

A Chronic Increase in Blood-Brain Barrier Permeability Facilitates Intraneuronal Deposition of Exogenous Bloodborne Amyloid-Beta1-42 Peptide in the Brain and Leads to Alzheimer's Disease-Relevant Cognitive Changes in a Mouse Model.

Background: Increased blood-brain barrier (BBB) permeability and amyloid-ß (Aß) peptides (especially Aß1-42) (Aß42) have been linked to Alzheimer's disease (AD) pathogenesis, but the nature of their involvement in AD-related neuropathological changes leading to cognitive changes remains poorly understood. Objective: To test the hypothesis that chronic extravasation of bloodborne Aß42 peptide and brain-reactive autoantibodies and their entry into the brain parenchyma via a permeable BBB contribute to AD-related pathological changes and cognitive changes in a mouse model. Methods: The BBB was rendered chronically permeable through repeated injections of Pertussis toxin (PT), and soluble monomeric, fluorescein isothiocyanate (FITC)-labeled or unlabeled Aß42 was injected into the tail-vein of 10-month-old male CD1 mice at designated intervals spanning ∼3 months. Acquisition of learned behaviors and long-term retention were assessed via a battery of cognitive and behavioral tests and linked to neuropathological changes. Results: Mice injected with both PT and Aß42 demonstrated a preferential deficit in the capacity for long-term retention and an increased susceptibility to interference in selective attention compared to mice exposed to PT or saline only. Immunohistochemical analyses revealed increased BBB permeability and entry of bloodborne Aß42 and immunoglobulin G (IgG) into the brain parenchyma, selective neuronal binding of IgG and neuronal accumulation of Aß42 in animals injected with both PT and Aß42 compared to controls. Conclusion: Results highlight the potential synergistic role of BBB compromise and the influx of bloodborne Aß42 into the brain in both the initiation and progression of neuropathologic and cognitive changes associated with AD.

Cancer immunotherapy via synergistic coactivation of myeloid receptors CD40 and Dectin-1.

Myeloid cells facilitate T cell immune evasion in cancer yet are pliable and have antitumor potential. Here, by cotargeting myeloid activation molecules, we leveraged the myeloid compartment as a therapeutic vulnerability in mouse models of pancreatic cancer. Myeloid cells in solid tumors expressed activation receptors including the pattern recognition receptor Dectin-1 and the TNF receptor superfamily member CD40. In mouse models of checkpoint inhibitor-resistant pancreatic cancer, coactivation of Dectin-1, via systemic ß-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors and induced immunological memory. Antitumor activity was dependent on cDC1s and T cells but did not require classical T cell-mediated cytotoxicity or blockade of checkpoint molecules. Rather, targeting CD40 drove T cell-mediated IFN-γ signaling, which converged with Dectin-1 activation to program distinct macrophage subsets to facilitate tumor responses. Thus, productive cancer immune surveillance in pancreatic tumors resistant to checkpoint inhibition can be invoked by coactivation of complementary myeloid signaling pathways.

Nanoscale, antigen encounter-dependent, IL-12 delivery by CAR T cells plus PD-L1 blockade for cancer treatment.

BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapies for the treatment of hematological malignancies experienced tremendous progress in the last decade. However, essential limitations need to be addressed to further improve efficacy and reduce toxicity to assure CAR-T cell persistence, trafficking to the tumor site, resistance to an hostile tumor microenvironment (TME), and containment of toxicity restricting production of powerful but potentially toxic bioproducts to the TME; the last could be achieved through contextual release upon tumor antigen encounter of factors capable of converting an immune suppressive TME into one conducive to immune rejection. METHODS: We created an HER2-targeting CAR-T (RB-312) using a clustered regularly interspaced short palindromic repeats (CRISPR) activation (CRISPRa) system, which induces the expression of the IL-12 heterodimer via conditional transcription of its two endogenous subunits p35 and p40. This circuit includes two lentiviral constructs. The first one (HER2-TEV) expresses an anti-human epidermal growth factor receptor 2 (HER2) CAR single chain variable fragment (scFv), with CD28 and CD3z co-stimulatory domains linked to the tobacco etch virus (TEV) protease and two single guide RNAs (sgRNA) targeting the interleukin (IL)-12A and IL12B transcription start site (TSS), respectively. The second construct (LdCV) encodes linker for activation of T cells (LAT) fused to nuclease-deactivated Streptococcus Pyogenes Cas9 (dCas9)-VP64-p65-Rta (VPR) via a TEV-cleavable sequence (TCS). Activation of the CAR brings HER2-TEV in close proximity to LdCV releasing dCas9 for nuclear localization. This conditional circuit leads to conditional and reversible induction of the IL-12/p70 heterodimer. RB-312 was compared in vitro to controls (cRB-312), lacking the IL-12 sgRNAs and conventional HER2 CAR (convCAR). RESULTS: The inducible CRISPRa system activated endogenous IL-12 expression resulting in enhanced secondary interferon (FN)-γ production, cytotoxicity, and CAR-T proliferation in vitro, prolonged in vivo persistence and greater suppression of HER2+ FaDu oropharyngeal cancer cell growth compared to the conventional CAR-T cell product. No systemic IL-12 was detected in the peripheral circulation. Moreover, the combination with programmed death ligand (PD-L1) blockade demonstrated robust synergistic effects. CONCLUSIONS: RB-312, the first clinically relevant product incorporating a CRISPRa system with non-gene editing and reversible upregulation of endogenous gene expression that promotes CAR-T cells persistence and effectiveness against HER2-expressing tumors. The autocrine effects of reversible, nanoscale IL-12 production limits the risk of off-tumor leakage and systemic toxicity.

Clinicians' Prediction of Survival and Prognostic Confidence in Patients with Advanced Cancer in Three East Asian Countries.

Background: Little is known about accuracy and confidence of clinicians' prediction of survival (CPS) in East-Asian countries. Objective: We aimed to examine accuracy of CPS for 7-, 21-, and 42-day survival in palliative inpatients and its association with prognostic confidence. Design: An international prospective cohort study in Japan (JP), Korea (KR), and Taiwan (TW). Setting/Subjects: Subjects were inpatients with advanced cancer admitted to 37 palliative care units in three countries. Measurements: Discrimination of CPS was investigated through sensitivity, specificity, overall accuracy, and area under the receiver operating characteristics curves (AUROCs) according to 7-, 21-, and 42-day survival. The accuracies of CPS were compared with those of Performance Status-based Palliative Prognostic Index (PS-PPI). Clinicians were instructed to rate confidence level on a 0-10-point scale. Results: A total of 2571 patients were analyzed. The specificity was highest at 93.2-100.0% for the 7-day CPS, and sensitivity was highest at 71.5-86.8% for the 42-day CPS. The AUROCs of the seven-day CPS were 0.88, 0.94, and 0.89, while those of PS-PPI were 0.77, 0.69, and 0.69 for JP, KR, and TW, respectively. As for 42-day prediction, sensitivities of PS-PPI were higher than those of CPS. Clinicians' confidence was strongly associated with the accuracy of prediction in all three countries (all p-values <0.01). Conclusions: CPS accuracies were highest (0.88-0.94) for the seven-day survival prediction. CPS was more accurate than PS-PPI in all timeframe prediction except 42-day prediction in KR. Prognostic confidence was significantly associated with the accuracy of CPS.

[Detection of Monosodium Urate Crystal of Hand and Wrist in Suspected Gouty Arthritis Patients on Dual-Energy CT and Relationship with Serum Urate Level]. / 손과 손목의 í†µí’ê´€ì ˆì—¼ì—ì„œ 이중에너지 CT를 이용한 요산나트륨 ê²°ì • 검출과 혈중 요산 농도와의 관계.

Purpose: We retrospectively investigated the characteristics of patients with monosodium urate (MSU) deposits of the hand and wrist on dual-energy CT (DECT) compared to those without. We also attempted to determine the pattern of MSU distribution in DECT. Materials and Methods: In total, 93 patients were included who had undergone DECT for evaluation of the hand or wrist pain under the clinical impression of gouty arthritis. The total volume of MSU deposits on DECT was calculated and the pattern of MSU distribution on DECT was analyzed. Also, the level of the serum urate at the time of DECT and the highest level of the serum urate of the patients were obtained from their records and the relationship between MSU and serum urate level was evaluated. Results: The range of the volume of MSU deposits on DECT was 0.01-16.11 cm3 (average: 1.07 cm3). The average level of serum urate was significantly higher in the MSU positive group than that in the MSU negative group. MSU deposits were most frequently observed in the wrists followed by fingers and digitorum tendons. Conclusion: On DECT, MSU deposits were most frequently detected in the wrist and related with high serum urate level.

Comparison of Objective Prognostic Score and Palliative Prognostic Score performance in inpatients with advanced cancer in Japan and Korea.

OBJECTIVE: Accurate prognostication is important for patients and their families to prepare for the end of life. Objective Prognostic Score (OPS) is an easy-to-use tool that does not require the clinicians' prediction of survival (CPS), whereas Palliative Prognostic Score (PaP) needs CPS. Thus, inexperienced clinicians may hesitate to use PaP. We aimed to evaluate the accuracy of OPS compared with PaP in inpatients in palliative care units (PCUs) in three East Asian countries. METHOD: This study was a secondary analysis of a cross-cultural, multicenter cohort study. We enrolled inpatients with far-advanced cancer in PCUs in Japan, Korea, and Taiwan from 2017 to 2018. We calculated the area under the receiver operating characteristics (AUROC) curve to compare the accuracy of OPS and PaP. RESULTS: A total of 1,628 inpatients in 33 PCUs in Japan and Korea were analyzed. OPS and PaP were calculated in 71.7% of the Japanese patients and 80.0% of the Korean patients. In Taiwan, PaP was calculated for 81.6% of the patients. The AUROC for 3-week survival was 0.74 for OPS in Japan, 0.68 for OPS in Korea, 0.80 for PaP in Japan, and 0.73 for PaP in Korea. The AUROC for 30-day survival was 0.70 for OPS in Japan, 0.71 for OPS in Korea, 0.79 for PaP in Japan, and 0.74 for PaP in Korea. SIGNIFICANCE OF RESULTS: Both OPS and PaP showed good performance in Japan and Korea. Compared with PaP, OPS could be more useful for inexperienced physicians who hesitate to estimate CPS.

The dynamic nature of the coronavirus receptor, angiotensin-converting enzyme 2 (ACE2) in differentiating airway epithelia.

Once inhaled, SARS-CoV-2 particles enter respiratory ciliated cells by interacting with angiotensin converting enzyme 2 (ACE2). Understanding the nature of ACE2 within airway tissue has become a recent focus particularly in light of the COVID-19 pandemic. Airway mucociliary tissue was generated in-vitro using primary human nasal epithelial cells and the air-liquid interface (ALI) model of differentiation. Using ALI tissue, three distinct transcript variants of ACE2 were identified. One transcript encodes the documented full-length ACE2 protein. The other two transcripts are unique truncated isoforms, that until recently had only been predicted to exist via sequence analysis software. Quantitative PCR revealed that all three transcript variants are expressed throughout differentiation of airway mucociliary epithelia. Immunofluorescence analysis of individual ACE2 protein isoforms exogenously expressed in cell-lines revealed similar abilities to localize in the plasma membrane and interact with the SARS CoV 2 spike receptor binding domain. Immunohistochemistry on differentiated ALI tissue using antibodies to either the N-term or C-term of ACE2 revealed both overlapping and distinct signals in cells, most notably only the ACE2 C-term antibody displayed plasma-membrane localization. We also demonstrate that ACE2 protein shedding is different in ALI Tissue compared to ACE2-transfected cell lines, and that ACE2 is released from both the apical and basal surfaces of ALI tissue. Together, our data highlights various facets of ACE2 transcripts and protein in airway mucociliary tissue that may represent variables which impact an individual's susceptibility to SARS-CoV-2 infection, or the severity of Covid-19.

"The surprise questions" using variable time frames in hospitalized patients with advanced cancer.

OBJECTIVE: Several studies supported the usefulness of "the surprise question" in terms of 1-year mortality of patients. "The surprise question" requires a "Yes" or "No" answer to the question "Would I be surprised if this patient died in [specific time frame]." However, the 1-year time frame is often too long for advanced cancer patients seen by palliative care personnel. "The surprise question" with shorter time frames is needed for decision making. We examined the accuracy of "the surprise question" for 7-day, 21-day, and 42-day survival in hospitalized patients admitted to palliative care units (PCUs). METHOD: This was a prospective multicenter cohort study of 130 adult patients with advanced cancer admitted to 7 hospital-based PCUs in South Korea. The accuracy of "the surprise question" was compared with that of the temporal question for clinician's prediction of survival. RESULTS: We analyzed 130 inpatients who died in PCUs during the study period. The median survival was 21.0 days. The sensitivity, specificity, and overall accuracy for the 7-day "the surprise question" were 46.7, 88.7, and 83.9%, respectively. The sensitivity, specificity, and overall accuracy for the 7-day temporal question were 6.7, 98.3, and 87.7%, respectively. The c-indices of the 7-day "the surprise question" and 7-day temporal question were 0.662 (95% CI: 0.539-0.785) and 0.521 (95% CI: 0.464-0.579), respectively. The c-indices of the 42-day "the surprise question" and 42-day temporal question were 0.554 (95% CI: 0.509-0.599) and 0.616 (95% CI: 0.569-0.663), respectively. SIGNIFICANCE OF RESULTS: Surprisingly, "the surprise questions" and temporal questions had similar accuracies. The high specificities for the 7-day "the surprise question" and 7- and 21-day temporal question suggest they may be useful to rule in death if positive.

Contextual reprogramming of CAR-T cells for treatment of HER2+ cancers.

BACKGROUND: Adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells combined with checkpoint inhibition may prevent T cell exhaustion and improve clinical outcomes. However, the approach is limited by cumulative costs and toxicities. METHODS: To overcome this drawback, we created a CAR-T (RB-340-1) that unites in one product the two modalities: a CRISPR interference-(CRISPRi) circuit prevents programmed cell death protein 1 (PD-1) expression upon antigen-encounter. RB-340-1 is engineered to express an anti-human epidermal growth factor receptor 2 (HER2) CAR single chain variable fragment (scFv), with CD28 and CD3ζ co-stimulatory domains linked to the tobacco etch virus (TEV) protease and a single guide RNA (sgRNA) targeting the PD-1 transcription start site (TSS). A second constructs includes linker for activation of T cells (LAT) fused to nuclease-deactivated spCas9 (dCas9)-Kruppel-associated box (KRAB) via a TEV-cleavable sequence (TCS). Upon antigen encounter, the LAT-dCas9-KRAB (LdCK) complex is cleaved by TEV allowing targeting of dCas9-KRAB to the PD-1 gene TSS. RESULTS: Here, we show that RB-340-1 consistently demonstrated higher production of homeostatic cytokines, enhanced expansion of CAR-T cells in vitro, prolonged in vivo persistence and more efficient suppression of HER2+ FaDu oropharyngeal cancer growth compared to the respective conventional CAR-T cell product. CONCLUSIONS: As the first application of CRISPRi toward a clinically relevant product, RB-340-1 with the conditional, non-gene editing and reversible suppression promotes CAR-T cells resilience to checkpoint inhibition, and their persistence and effectiveness against HER2-expressing cancer xenografts.

Determination of Residual Triflumezopyrim Insecticide in Agricultural Products through a Modified QuEChERS Method.

A rapid and simple analytical method for triflumezopyrim, a new class of mesoionic insecticides and commercialized molecules from DuPont, was developed with a modified QuEChERS method. The pH adjustment was used to improve the extraction efficiency of acetonitrile solvent, and dispersive solid-phase extraction was employed for the clean-up process. The five selected food commodities were used to verify the present optimized method, which displayed good linearity with an excellent correlation coefficient (R2 = 0.9992-0.9998) in the 0.003-0.30 mg/kg calibration range. The method limits of detection (LOD) and quantification (LOQ) were determined to be a value of 0.003 and 0.01 mg/kg, respectively. The mean recovery for the triflumezopyrim was in the 89.7-104.3% range. The relative standard deviations were ≤9.8% for intra- (n = 5) and inter-day (n = 15) precisions at concentrations of 0.01, 0.1, and 0.5 mg/kg in the five representative samples. The matrix effect has been calculated to confirm the effect during ionization of the analyte in the UPLC-MS/MS. The matrix effects of the instrumental analysis showed that triflumezopyrim was less susceptible to matrices. The proposed analytical method in this study has effectively improved the accuracy, selectivity, and sensitivity for the determination of triflumezopyrim in agricultural commodities; therefore, it can serve as a reference method for the establishment of maximum residue limits (MRLs).

The Effect of Mechanical Tongue Cleaning on Oral Malodor and Tongue Coating.

BACKGROUND: Mechanical tongue cleaning is an important oral hygiene procedure; it is known that a significant cause of volatile sulfur compounds (VSCs), a major component of bad breath, is due to the bacteria coating the tongue. This study was conducted to identify the effect of mechanical tongue cleaning on reducing bad breath and tongue coating. METHODS: Various mechanical tongue-cleaning methods were studied, including removing tongue coating using a toothbrush, removing tongue coating using a tongue scraper, and removing tongue coating using a toothbrush and a tongue scraper together. The results were as follows. RESULTS: First, the organic bad breath measurement value after cleaning the tongue significantly decreased in the group using only the toothbrush, the group using only the tongue scraper, and the group using both the toothbrush and the tongue scraper. However, there was no difference between the groups. Second, after cleaning the tongue, the measured values of the tongue coating in the values of WTCI (Winkel's tongue coating index) and Qray view were significantly reduced in all three groups, and there was no difference between the groups. Third, the gas measurement value in the oral cavity using a machine significantly decreased only the H2S value of the group using the tongue scraper immediately after the mechanical tongue cleaning. CONCLUSIONS: From these results, it can be confirmed that mechanical tongue cleaning is effective at reducing bad breath and tongue coating. However, in this study, there was no difference in the reduction effect according to the tools (groups) used for mechanical tongue cleaning. It can therefore be seen that wiping accurately from the rear of the tongue to the front is more effective at reducing bad breath and tongue coating.

Sarcopenia and Hip-Structure Analysis Variables in Korean Elderly Population.

The purpose of this study is comparing the hip-structure analysis (HSA) variables with the skeletal muscle index (SMI) in elderly patients with sarcopenia using nationwide representative data on the Republic of Korea (ROK). The survey data were collected from household interviews and direct standardized physical examinations conducted in specially equipped mobile examination centers. The data were collected in 2008 from 9744 participants. Patients under 65 years of age who were without data on the skeletal-muscle-mass and HSA variables were excluded. After these exclusions, a total of 744 participants (293 men and 451 women) were ultimately analyzed. The HSA measurements of the hip-bone geometry were analyzed using dual-energy X-ray absorptiometry. The appendicular SMI is defined as the sum of the arm and leg SMIs. Sarcopenia is defined according to the criteria for the Asia Working Group for Sarcopenia as SMIs of less than 5.4 kg/m2 and 7.0 kg/m2 for women and men, respectively. In the entire population, SMI was found to be positively correlated to HSA variables. After adjusting for age, body mass index, and energy intake in both the women and men groups, a statistically significant difference became evident in all variables between the SMI and the HSA. The present study suggests that skeletal-muscle loss negatively affects hip-bone-strength indices in elderly sarcopenia patients. Implementing strategies to increase SMI in the elderly population may be useful for reducing the vulnerability to hip fracture.

Repetitive Transcranial Magnetic Stimulation Enhances Recovery in Central Cord Syndrome Patients.

OBJECTIVE: To investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on neurological and functional recovery in patients with central cord syndrome (CCS) involving the upper extremities between the treated and non-treated sides of the treated group and whether the outcomes are comparable to that of the untreated control group. METHODS: Nineteen CCS patients were treated with high-frequency (20 Hz) rTMS over the motor cortex for 5 days. The stimulation side was randomly selected, and all the subjects received conventional occupational therapy during the rTMS-treatment period. Twenty CCS patients who did not receive rTMS were considered as controls. Clinical assessments, including those by the International Standard for Neurological Classification of Spinal Cord Injury, the Jebsen-Taylor Hand Function Test, and the O'Connor Finger Dexterity Test were performed initially and followed up for 1 month after rTMS treatment or 5 weeks after initial assessments. RESULTS: The motor scores for upper extremities were increased and the number of improved cases was greater for the treated side in rTMS-treated patients than for the non-treated side in rTMS-treated patients or controls. The improved cases for writing time and score measured on the Jebsen-Taylor Hand Function Test were also significantly greater in number on the rTMS-treated side compared with the non-treated side and controls. There were no adverse effects during rTMS therapy or the follow-up period. CONCLUSION: The results of the application of high-frequency rTMS treatment to CCS patients suggest that rTMS can enhance the motor recovery and functional fine motor task performance of the upper extremities in such individuals.

Optimization of Large-Scale Expansion and Cryopreservation of Human Natural Killer Cells for Anti-Tumor Therapy.

Allogeneic natural killer (NK) cell therapy is a potential therapeutic approach for a variety of solid tumors. We established an expansion method for large-scale production of highly purified and functionally active NK cells, as well as a freezing medium for the expanded NK cells. In the present study, we assessed the effect of cryopreservation on the expanded NK cells in regards to viability, phenotype, and anti-tumor activity. NK cells were enormously expanded (about 15,000-fold expansion) with high viability and purity by stimulating CD3+ T cell-depleted peripheral blood mononuclear cells (PBMCs) with irradiated autologous PBMCs in the presence of IL-2 and OKT3 for 3 weeks. Cell viability was slightly reduced after freezing and thawing, but cytotoxicity and cytokine secretion were not significantly different. In a xenograft mouse model of hepatocellular carcinoma cells, cryopreserved NK cells had slightly lower anti-tumor efficacy than freshly expanded NK cells, but this was overcome by a 2-fold increased dose of cryopreserved NK cells. In vivo antibody-dependent cell cytotoxicity (ADCC) activity of cryopreserved NK cells was also demonstrated in a SCID mouse model injected with Raji cells with rituximab co-administration. Therefore, we demonstrated that expanded/frozen NK cells maintain viability, phenotype, and anti-tumor activity immediately after thawing, indicating that expanded/frozen NK cells can provide 'ready-to-use' cell therapy for cancer patients.

Malnutrition and chronic inflammation as risk factors for sarcopenia in elderly patients with hip fracture.

BACKGROUND AND OBJECTIVES: To evaluate malnutrition and chronic inflammation as risk factors for sarcopenia in elderly patients with hip fractures, as defined by the criteria of the Asian Working Group on Sarcopenia (AWGS). METHODS AND STUDY DESIGN: A total of 327 elderly patients with hip fractures were enrolled in this retrospective observational study. The main outcome measure was the nutritional status and nutritional risk factors for sarcopenia in elderly patients. Diagnosis of sarcopenia was made according to the guidelines of the AWGS. Whole body densitometry analysis was used to measure skeletal muscle mass, and muscle strength was evaluated by handgrip testing. Multivariable regression analysis was utilized to analyze the nutritional risk factors for sarcopenia in patients with hip fractures. RESULTS: Of 327 patients with hip fractures (78 men and 249 women), the prevalence of sarcopenia was 60.3% and 30.1% in men and women, respectively. The rates of three indicators of malnutrition in men and women (low BMI, hypoalbuminemia, and hypoproteinemia) in sarcopenia patients with hip fractures were 23.4%, 31.9%, and 53.2% and 21.3%, 21.3%, and 37.3%, respectively. The prevalence of markers of chronic inflammation (increased CRP and ESR) in men and women with sarcopenia and hip fractures were 74.9% and 52.2%, and 49.3% and 85.1%, respectively. After adjusting for covariates, low BMI and hypoproteinemia in women were associated with a 2.9- and 2.1-fold greater risk of sarcopenia than non-sarcopenia, respectively. CONCLUSIONS: The present study revealed a strong relationship between sarcopenia and malnutrition and chronic inflammatory factors in elderly patients with hip fractures.

Relationship between water intake and skeletal muscle mass in elderly Koreans: A nationwide population-based study.

OBJECTIVES: The purposes of this study were to evaluate the correlation between sarcopenia and water intake and investigate lack of daily water intake in the presence of sarcopenia in an elderly population. METHODS: Data from 3656 participants (1582 men and 2074 women) were analyzed using the Korea National Health and Nutrition Examination Survey. Sarcopenia was defined in accordance with the criteria of the Asia Working Group for Sarcopenia. Water intake was assessed using the dietary water adequacy ratio and was calculated by dividing the daily water intake from fluid by the recommended daily amount of 1000 mL in men and 900 mL in women. RESULTS: Water intake from food (g/d and cup/d) and dietary water adequacy ratio (mL) were significantly lower in the sarcopenia group (757.8 g, 890.1 g, and 0.74 mL in men; 511.9 g, 757.8 g, and 0.70 mL in women, respectively) than in the non-sarcopenia group (878.4 g, 1015.1 g, and 0.81 mL in men; 581.3 g, 790.5 g, 0.74 mL in women, respectively). In elderly men, the odds ratio of sarcopenia in the lowest quartile increased to 1.47 (range, 1.13-1.91) in Model 2 compared with that in the highest quartile. In elderly women, the odds ratio of sarcopenia in the lowest quartile increased to 1.50 (range, 1.08-2.08) in Model 2 compared with that in the highest quartile. CONCLUSIONS: The prevalence of sarcopenia in the elderly population was related to inadequate dietary water intake after adjusting for covariates. Adequate water intake in the elderly should be recommended to prevent dehydration-related complications, including sarcopenia.

Mean Hand Grip Strength and Cut-off Value for Sarcopenia in Korean Adults Using KNHANES VI.

The purpose of this study was to report age- and gender-specific distribution of the hand grip strength (HGS) using data from the Korea National Health and Nutrition Examination Survey (KNHANES) VI-3 (2015) survey and determine cut-off values for low muscle strength of HGS of Koreans. Of a total of 7,380 participants, 4,553 were subjected to measurements of HGS, including 1,997 men and 2,556 women with a mean age of 49.3 years (range, 19-80 years). The mean ages of men and women were 49.0 and 49.5 years, respectively. HGS was measured using a digital hand dynamometer. It was defined as maximal measured grip strength of the dominant hand. The cut-off value for low muscle strength was defined as the lower 20th percentile of HGS of the study population. Maximum grip strength of men was significantly higher than that of women (40.2 kg in men vs. 24.2 kg in women, P < 0.001). The mean HGS was increased from the age of 19 to 39 years. It was peaked in the age of 35 to 39 years range for both men and women. It was then decreased after 39 years. The cut-off values of HGS in male and female elderly healthy populations were 28.6 and 16.4 kg, respectively. These data might be used as reference values when evaluating sarcopenia and assessing hand injuries.

Fanconi anemia protein FANCD2 is activated by AICAR, a modulator of AMPK and cellular energy metabolism.

FANCD2 is a pivotal molecule in the pathogenesis of Fanconi anemia (FA), an autosomal recessive human syndrome with diverse clinical phenotypes, including cancer predisposition, short stature, and hematological abnormalities. In our previous study, we detected the functional association of FANC proteins, whose mutations are responsible for the onset of FA, with AMPK in response to DNA interstrand crosslinking lesions. Because AMPK is well known as a critical sensing molecule for cellular energy levels, we checked whether FANCD2 activation occurs after treatments affecting AMPK and/or cellular energy status. Among the treatments tested, AMPK-activating 5-aminoimidazole-4-carboxamide-ribonucleoside (AICAR) induced monoubiquitination and nuclear foci formation of FANCD2, which are biomarkers of FANCD2 activation. FANCD2 activation was abolished by treatments with Compound C, an AMPK inhibitor, or after AMPKα1 knockdown, substantiating the involvement of AMPK in AICAR-induced FANCD2 activation. Similarly, FANCA protein, which is a component of the FA core complex monoubiquitinating FANCD2, was required for this event. Furthermore, FANCD2 repression enhanced cell death upon AICAR treatments in transformed fibroblasts and cell cycle arrest in the renal cell carcinoma cell line Caki-1. Overall, this study showed FANCD2 involvement in response to AICAR, a chemical modulating cellular energy metabolism.