Chalcone-Monoterpene Derivatives from the Buds of Cleistocalyx operculatus and Their Potential as Protein Tyrosine Phosphatase 1B Inhibitors.

Four new compounds, racemic chalcone-monoterpene hybrids (1-3) and a chalcone (9), along with nine known compounds (4-8, 10-13), have been isolated from the buds of Cleistocalyx operculatus. The chemical structures of the isolated compounds were identified through NMR data analysis and confirmed by computational methods, including electronic circular dichroism (ECD) calculations, and further synthetic approaches. Compounds 1-5 were synthesized via a Diels-Alder reaction, a process informed by biomimetic condensation studies that combined chalcones and monoterpenes. These synthetic approaches also yielded various unnatural chalcone-monoterpene derivatives (14-23). The inhibitory effects on protein tyrosine phosphatase 1B (PTP1B) of both naturally isolated and synthetically obtained compounds were evaluated. Compounds 4, 9, 13, and 16b exhibited potent PTP1B inhibitory activity, with IC50 values ranging from 0.9 ± 0.2 to 3.9 ± 0.7 µM. The enantiomers (+)-4 and (-)-16b showed enhanced activity compared to their respective enantiomers. Kinetic studies indicate that all active compounds inhibit PTP1B through mixed mechanisms, and molecular docking simulations agree with the experimental assays on PTP1B. Our results suggest that chalcone-meroterpene adducts from the buds of C. operculatus exhibit potential as antidiabetic agents, partly due to their PTP1B enzyme inhibition.

Determination of tacrolimus in human whole blood in kidney transplant recipients using a rapid and specific LC-MS/MS method.

OBJECTIVE: To develop and validate an LC-M/SMS method for the determination of tacrolimus in human whole blood. METHOD: The LC-MS/MS method for the determination of tacrolimus in whole blood was developed and validated according to the guidelines. Concentrations of TAC in 100 kidney transplant patients measured by LC-MS/MS were compared with CMIA using correlation analysis and Bland-Altman plots. RESULTS: The method had a total chromatographic run time of 5 min. The calibration curves were linear over the range of 0.5-100.0 ng/mL with a lower limit of quantification of 1 ng/mL. The intra- and interday accuracy was within the range of 93.3%-109.2% and 96.0%-108.4%, respectively, with precision ranging from 0.8 to 9.4%. The mean extraction recoveries of TAC ranged from 102.6 to 107.8%. The mean concentrations of TAC in whole blood of kidney transplant patients measured by the two assays were different at 1, 3 months and all time points (p < 0.001), but no significant difference was observed at 6 months (p = 0.094). The correlation of data was good with the correlation coefficients (r2 ) of 0.7581, 0.8811, 0.8777, and 0.8077, respectively. Passing-Bablok regression analysis demonstrated good correlations with r2 values higher than 0.88 between TAC levels measured by LC-MS/MS and CMIA. Using Bland-Altman plots yielded average biases of 1.29, 0.79, 0.11, and 0.65 ng/mL at 1, 3, and 6 months and all time points. CONCLUSION: The LC-MS/MS method was validated for the accurate determination of TAC in human whole blood. The comparison of tacrolimus concentrations measured by the LC-MS/MS with CMIA showed a good correlation and agreement of two methods, suggesting LC-MS/MS should be used routinely to monitor TAC concentrations in kidney transplant patients.

Bach Mai Procedure for complete mesocolic excision, central vascular ligation, and D3 lymphadenectomy in total laparoscopic right hemicolectomy: a prospective study.

PURPOSE: Total laparoscopic right hemicolectomy with complete mesocolic excision (CME), central vascular ligation (CVL), and D3 lymphadenectomy is still the most challenging colon procedures for gastrointestinal surgeons. We herein report the technical details and our preliminary experience of Bach Mai Procedure - a novel-combining (cranial, medial to lateral, and caudal) approach with early resection of the terminal ileum. METHODS: The dissection stage was central vascular isolation and ligation by a combined multiple approaches in the following four steps: cranial approach, dissecting along the inferior aspect of pancreatic isthmus to reveal the middle colic vessels and the anterior aspect of the superior mesentery vein and then exposed the right gastroepiploic vein and the trunk of Henle; medial-to-lateral approach, exposing the surgical axis - the superior mesenteric vascular axis and then early resection of the terminal ileum to open the dissection from the bottom up; and caudal approach, radical ligation of the ileocecal artery and right colic artery (central vascular ligation), lymph node dissection (D3 lymphadenectomy), and resecting the Toldt fascia of the colon to release the entire right colon from the abdominal wall. RESULTS: In 12 months, there were 32 cases of primary right-sided colon malignancies that have undergone tLRHD3, CME/CVL based on the Bach Mai Procedure. In 3 cases (9.4%), the tumor site was hepatic flexure. The median of lymph node number (LNN) was 38, with the maximum number which was 101. No serious postoperative complications (grade 3 or higher) neither inhospital mortality was detected. CONCLUSION: This Bach Mai procedure, a novel-combining approach with early resection of the terminal ileum, is technically feasible and safe for tLRHD3, CME/CVL. Further investigations and follow-up must be proceeded to evaluate the long-term outcomes of our technique.

Isolated complete caudate lobectomy with Glissonean pedicle isolation using Takasaki's technique and right-left approach: preliminary experience from two case reports.

BACKGROUND: Tumors located in the caudate lobe may be primary tumor or metastases from other sites. Isolated caudate lobectomy (ICL) is a challenging procedure due to its complex structure and location. The access route to the caudate lobe has an important role in the success of the operation. METHODS: Based on the characteristics of the segment I location, which is the part of the liver located in front of the vena cava, below the hepatic veins, and cranial to the hilar plate, our approach aims to isolate the entire caudate lobe from these anatomical structures with the following steps: dissecting the caudate lobe from the hilar plate and isolating the caudate lobe from the IVC and from the hepatic veins along with parenchymal resection. RESULTS: We report two successful cases with the Glissonean pedicle transection method described by Takasaki and the combined right- and left-side approach: a 63-year-old female patient with a 46-mm-in-diameter HCC tumor and a 39-year-old female patient with a 45-mm lesion and the pathological result was focal nodular hyperplasia. CONCLUSIONS: We found this to be a safe and effective approach, which can be applied to all cases of benign tumors or in the case of malignant tumors located entirely in the caudate lobe when extended hepatic resection is not possible due to poor liver function or small remnant liver volume.

Anti-Diabetes, Anti-Gout, and Anti-Leukemia Properties of Essential Oils from Natural Spices Clausena indica, Zanthoxylum rhetsa, and Michelia tonkinensis.

Essential oils (EOs) of Clausena indica fruits, Zanthoxylum rhetsa fruits, and Michelia tonkinensis seeds were analyzed for their phytochemical profiles and biological activities, including anti-diabetes, anti-gout, and anti-leukemia properties. Sixty-six volatile compounds were identified by gas chromatography-mass spectrometry (GC-MS), in which, myristicin (68.3%), limonene (44.2%), and linalool (49.3%) were the most prominent components of EOs extracted from C. indica, Z. rhetsa, and M. tonkinensis, respectively. In addition, only EOs from C. indica inhibited the activities of all tested enzymes comprising α-amylase (IC50 = 7.73 mg/mL), α-glucosidase (IC50 = 0.84 mg/mL), and xanthine oxidase (IC50 = 0.88 mg/mL), which are related to type 2 diabetes and gout. Remarkably, all EOs from C. indica, Z. rhetsa (IC50 = 0.73 mg/mL), and M. tonkinensis (IC50 = 1.46 mg/mL) showed a stronger anti-α-glucosidase ability than acarbose (IC50 = 2.69 mg/mL), a known anti-diabetic agent. Moreover, the growth of leukemia cell Meg-01 was significantly suppressed by all EOs, of which, the IC50 values were recorded as 0.32, 0.64, and 0.31 mg/mL for EOs from C. indica, Z. rhetsa, and M. tonkinensis, respectively. As it stands, this is the first report about the inhibitory effects of EOs from C. indica and Z. rhetsa fruits, and M. tonkinensis seeds on the human leukemia cell line Meg-01 and key enzymes linked to diabetes and gout. In conclusion, the present study suggests that EOs from these natural spices may be promising candidates for pharmaceutical industries to develop nature-based drugs to treat diabetes mellitus or gout, as well as malignant hematological diseases such as leukemia.

Effects of In Vitro Digestion on Anti-α-Amylase and Cytotoxic Potentials of Sargassum spp.

This is the first study to examine the effects of in vitro digestion on biological activities of Sargassum spp., a broadly known brown seaweed for therapeutic potential. Three fractions (F1-F3) were obtained from hexane extract by column chromatography. Under in vitro simulated digestion, the anti-α-amylase capacity of F1 in oral and intestinal phases increases, while it significantly decreases in the gastric phase. The α-amylase inhibition of F2 promotes throughout all digestive stages while the activity of F3 significantly reduces. The cytotoxic activity of F1 against U266 cell-line accelerates over the oral, gastric, and intestinal stages. The fractions F2 and F3 exhibited the declined cytotoxic potentialities in oral and gastric phases, but they were strengthened under intestinal condition. Palmitic acid and fucosterol may play an active role in antidiabetic and cytotoxic activity against multiple myeloma U266 cell line of Sargassum spp. However, the involvement of other phytochemicals in the seaweed should be further investigated.

Cytotoxicity of Callerya speciosa Fractions against Myeloma and Lymphoma Cell Lines.

Callerya speciosa is widely distributed in tropical and subtropical countries and is traditionally used for preventing numerous disorders. In this study, a bioguided fractionation of ethyl acetate extract (SE) from C. speciosa root was carried out to target antioxidant and cytotoxic activities. Of the four fractions (SE1-SE4) obtained by column chromatography, SE4 had the strongest anti-radical ability in the DPPH and ABTS assays (IC50 = 0.05 and 0.17 mg/mL, respectively), with results close to butylated hydroxytoluene (BHT), a common antioxidant agent. The cytotoxic activities against the selected cells were analyzed in this study by MTT assay. Accordingly, SE2, SE3, and SE4 significantly inhibited the viability of multiple myeloma cell lines, comprising U266 (IC50 = 0.38, 0.09, and 0.11 mg/mL, respectively) and KMS11 (IC50 = 0.09, 0.17, and 0.15 mg/mL, respectively), mantle cell lymphoma Mino (IC50 = 0.08, 0.16, and 0.15 mg/mL, respectively), and the noncancerous cell line LCL (IC50 = 0.40, 0.32, and 0.21 mg/mL, respectively). At a concentration of 125 µg/mL, SE2, SE3, and SE4 induced the cell apoptosis of U266 (32.2%, 53.2%, and 55.6%, respectively), KMS11 (36.9%, 40.8%, and 47.9%, respectively), Mino (36.6%, 39.8%, and 22.0%, respectively), and LCL (12.4%, 17.5%, and 23.5%, respectively) via annexin V assay. The dominant compounds detected in fractions by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS), were identified as isoflavones. This is the first report describing C. speciosa as a promising natural source of antileukemia and antimyeloma agents, which may be useful for the development of blood cancer treatments.

Donor UNC-93 Homolog B1 genetic polymorphism predicts survival outcomes after unrelated bone marrow transplantation.

UNC-93 homolog B1 (UNC93B1) is a key regulator of toll-like receptors (TLRs), pattern recognition receptors that sense invading pathogens and manage the innate immune response and deliver them from the endoplasmic reticulum to their respective endosomal signaling compartments. Several types of TLRs are known to contribute to the inflammatory process after allogeneic hematopoietic stem cell transplantation (SCT), so UNC93B1 might play integral roles there. We investigated the influence of the UNC93B1 single-nucleotide polymorphism (SNP) rs308328 (T>C) on transplant outcomes in a cohort of 237 patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor UNC93B1 C/C genotype was associated with a better 3-year overall survival than the donor UNC93B1 C/T or T/T genotype. An analysis of the UNC93B1 rs308328 genotype may therefore be useful for selecting the donor, estimating the prognosis, and creating therapeutic strategies after allogeneic SCT.

Pretreatment Immature Platelet Fraction as a Surrogate of Reticulated Platelets Predicts the Response to Corticosteroids in Adults with Immune Thrombocytopenia.

OBJECTIVES: Reticulated platelets circulating in the blood reflect megakaryopoietic activity and platelet turnover and can be automatically and low-invasively measured as the immature platelet fraction (IPF) using a Sysmex XN hematocytometer. The present study retrospectively investigated whether or not the IPF can predict the treatment response to corticosteroids in adult patients with primary immune thrombocytopenia (ITP). METHODS: Forty-six patients who had been newly diagnosed with primary treatment-naïve ITP and started treatment with corticosteroids were analyzed. RESULTS: Among the 46 primary ITP patients, 33 (72%) responded to the treatment and 13 (28%) did not. The percentage of IPF (IPF%) among the nonresponders was significantly lower than that of the responders (6.6 vs. 16.0%; p < 0.001). In the receiver operating characteristics analysis, the optimum IPF% cut-off value for predicting the treatment response was 12%, with a specificity of 85% and a sensitivity of 76%. CONCLUSIONS: Our findings thus suggest that measuring the IPF% as a surrogate of reticulated platelets is useful to identify patients likely to respond to corticosteroids.

Safety climate, leadership and patient views associated with hip fracture care quality and clinician perceptions of hip fracture care performance.

BACKGROUND: Hip fracture is a major public health concern for older adults, requiring surgical treatment for patients presenting at hospitals across Australia. Although guidelines have been developed to drive appropriate care of hip fracture patients in hospitals, data on health outcomes suggest these are not well-followed. OBJECTIVE: This study aims to examine whether clinician measures of safety, teamwork and leadership, and patient perceptions of care are associated with key indicators of hip fracture care and the extent to which there is agreement between clinician perceptions of hip fracture care performance and actual hospital performance of hip fracture care. METHODS: Retrospective analysis was performed on a series of questionnaires used to assess hospital department- and patient-level measures from the Deepening our Understanding of Quality in Australia study. Data were analysed from 32 public hospitals that encompassed 23 leading hip fracture clinicians, 716 patient medical records and 857 patients from orthopaedic public hospital wards. RESULTS: Aggregated across all hospitals, only 5 of 12 of the key hip fracture indicators had ≥50% adherence. Adherence to indicators requiring actions to be performed within a recommended time period was poor (7.2-25.6%). No Patient Measure of Safety or clinician-based measures of teamwork, safety climate or leadership were associated with adherence to key indicators of hip fracture care. Simple proportionate agreement between clinician perceptions and actual hospital performance was generally strong, but few agreement coefficients were compelling. CONCLUSION: The development of strong quality management processes requires ongoing effort. The findings of this study provide important insights into the relationship between hospital care and outcomes for hip fracture patients and could drive the design of targeted interventions for improved quality assurance of hip fracture care.

The Impact of NLRP3 Activation on Hematopoietic Stem Cell Transplantation.

NLR family pyrin domain-containing 3 (NLRP3) is an intracellular protein that after recognizing a broad spectrum of stressors, such as microbial motifs and endogenous danger signals, promotes the activation and release of the pro-inflammatory cytokines IL-1ß and IL-18, thus playing an essential role in the innate immune response. Several blood cell types, including macrophages, dendritic cells, and hematopoietic stem and progenitor cells (HSPCs), express NLRP3, where it has been implicated in various physiological and pathological processes. For example, NLRP3 participates in the development and expansion of HSPCs, and their release from bone marrow into the peripheral blood has been implicated in certain hematological disorders including various types of leukemia. In addition, accumulating evidence indicates that activation of NLRP3 plays a pivotal role in the development of transplant complications in patients receiving hematopoietic stem cell transplantation (HSCT) including graft versus host disease, severe infections, and transplant-related mortality. The majority of these complications are triggered by the severe tissue damage derived from the conditioning regimens utilized in HSCT which, in turn, activates NLRP3 and, ultimately, promotes the release of proinflammatory cytokines such as IL-1ß and IL-18. Here, we summarize the implications of NLRP3 in HSCT with an emphasis on the involvement of this inflammasome component in transplant complications.

Management of Acute Central Retinal Artery Occlusion, a "Retinal Stroke": An Institutional Series and Literature Review.

OBJECTIVES: Acute central retinal artery occlusion (CRAO) is an ophthalmologic emergency that often results in permanent vision loss. Over 25% are associated with acute cerebral ischemia. In the absence of existing Level I treatment options, this study aims to examine institutional practice patterns and review the literature to develop a formalized approach to the treatment of CRAO in the era of ischemic stroke protocols. MATERIALS AND METHODS: This is a retrospective review of institutional practices in the workup and treatment of patients diagnosed with acute non-arteritic (NA) CRAO at a single center from January 2017 to August 2020. RESULTS: Of 91 patients managed for acute NA-CRAO, 62.6% were male and average age was 66.4 years. Only 20.9% of patients presented within 4 h of symptom onset. 12.1% of patients had evidence of acute stroke on MRI, and 27.5% had ipsilateral internal carotid artery stenosis >50%. Half (52.7%) did not receive any acute treatment for CRAO, excluding antiplatelet/anticoagulation. 48.5% of patients undergoing acute medical treatment had improved visual acuity compared to 29.4% without treatment (p=0.14). CONCLUSIONS: There is a lack of clear protocol for the management of NA-CRAO. While not reaching statistical significance, our experience mirrors the literature with patients undergoing medical treatment demonstrating improved visual acuity over those without treatment. Given the presence of acute ischemic stroke, carotid disease, and/or stroke risk factors in over 25% of patients with CRAO, multidisciplinary involvement and modern stroke algorithms should be considered for this disease.

Government financial support and firm productivity in vietnam.

Using the Färe-Primont index and instrumental variable fixed effect estimation for the data of small and medium-sized enterprises (SMEs), this study considers if receiving government financial support enables SMEs in Vietnam to become more productive. The paper discovers no evidence of linkage between financial support and firm productivity. However, access to financial support improves technological progress and growth in firm scale but has a negative effect on improvement in technical efficiency. The estimation results reveal that the use of productivity as an aggregated index in previous studies may hide the real effect of government support on firm productivity.

Neutralizing Antibodies against Enteroviruses in Patients with Hand, Foot and Mouth Disease.

Hand, foot and mouth disease (HFMD) is an emerging infection with pandemic potential. Knowledge of neutralizing antibody responses among its pathogens is essential to inform vaccine development and epidemiologic research. We used 120 paired-plasma samples collected at enrollment and >7 days after the onset of illness from HFMD patients infected with enterovirus A71 (EV-A71), coxsackievirus A (CVA) 6, CVA10, and CVA16 to study cross neutralization. For homotypic viruses, seropositivity increased from <60% at enrollment to 97%-100% at follow-up, corresponding to seroconversion rates of 57%-93%. Seroconversion for heterotypic viruses was recorded in only 3%-23% of patients. All plasma samples from patients infected with EV-A71 subgenogroup B5 could neutralize the emerging EV-A71 subgenogroup C4. Collectively, our results support previous reports about the potential benefit of EV-A71 vaccine but highlight the necessity of multivalent vaccines to control HFMD.

Biallelic loss of FAM46C triggers tumor growth with concomitant activation of Akt signaling in multiple myeloma cells.

Loss of heterozygosity or mutation of the family with sequence similarity 46, member C (FAM46C) gene on chromosome band 1p12 is associated with shorter overall survival of patients with multiple myeloma (MM). In this study, using human MM cell lines (KMS-11, OCI-My5, and ANBL-6), we generated FAM46C-/- cell clones and examined the effect of disruption of FAM46C on cell survival and cellular signaling. Cell proliferation assays showed increased clonogenicity of FAM46C-/- KMS-11 cells compared to WT cells. Xenograft experiments showed significantly shorter overall survival of mice harboring the FAM46C-/- cell-derived tumors than mice with the FAM46CWT cell-derived tumors. Notably, levels of phosphorylated Akt and its substrates increased both in vitro and in vivo in the FAM46C-/- cells compared to WT cells. In addition, caspase activities decreased in the FAM46C-/- cells. Results of gene set enrichment analysis showed that loss of FAM46C significantly activated serum-responsive genes while inactivating phosphatase and tensin homolog (PTEN)-related genes. Mechanistically, loss of FAM46C decreased the PTEN activity, number of apoptotic cells, and caspase activities. PF-04691502, a selective PI3K inhibitor, suppressed the augmented phosphorylation of Akt and its substrate FoxO3a. Treatment with afuresertib (a specific Akt inhibitor) in combination with bortezomib additively decreased FAM46C-/- MM cell survival. Collectively, this study is the first to report that loss of FAM46C triggers the concomitant activation of the PI3K-Akt signaling pathway, which might be a therapeutic target for MM with abnormalities in the FAM46C gene.

Perpetration of Intimate Partner Violence Among Men Living with HIV in Northern Vietnam.

We examined the prevalence of intimate partner violence (IPV) perpetration and characteristics of HIV-infected male perpetrators. The cross-sectional study was conducted in Vietnam with male antiretroviral treatment clients (N = 1099; mean age = 40.2 years). Bivariable associations were tested between psychological or physical/sexual IPV perpetration in the last 12 months and sociodemographic, psychosocial, and sexual behavioral factors using prevalence ratios. Factors significant at p < 0.10 were entered in multivariable models for each IPV outcome using a modified Poisson approach. Results showed 15.6% (N = 171/1099) reported perpetrating psychological IPV and 7.6% (N = 84/1099) perpetrating physical/sexual IPV in the last 12 months. HIV risk behaviors, including hazardous drinking and multiple sexual partners, having witnessed interparental violence as a child, and depressive symptoms were associated with perpetrating IPV. HIV interventions targeting HIV-infected men in Vietnam should intervene on IPV perpetration by addressing the co-occurring factors of sexual risk, depression, alcohol use, and child maltreatment that are correlated with IPV.

Are cataract surgery referrals to public hospitals in Australia poorly targeted?

IMPORTANCE: Referral letters constitute the first step on the pathway to cataract surgery; however, little is known on how effective referral letters are in providing adequate information to triage patients and inform surgical prioritization. BACKGROUND: Benchmarking exercises are important to document referral processes and to identify areas where improvements can be made. DESIGN: Cross-sectional study with longitudinal follow-up conducted at two metropolitan public hospitals in New South Wales, Australia. PARTICIPANTS: A total of 400 sequential cataract referral letters. METHODS: An audit of cataract referral letters was performed and content benchmarked against international prioritization tools. Medical records were reviewed 1 year following referral. MAIN OUTCOME MEASURES: Referral quality and waiting times. RESULTS: Two-thirds of patients referred for cataract surgery were yet to have their initial hospital appointment in the year following referral (65%, 245/376). One half of referrals seen in clinic (49%, 64/113) were not listed for cataract surgery. Multivariate analysis revealed referral letter content was not indicative of surgical booking, with the major predictors being hospital-recorded visual acuity and grading of cataract (P < 0.0001). Referral content lacked sufficient detail to apply prioritization tools developed in other settings. CONCLUSION AND RELEVANCE: This audit highlights a disconnect between referral letter content and hospital assessment of patients. Current referrals to public hospitals are poorly targeted, with high numbers of referred patients not proceeding to surgery. Patients commonly waited over 1 year to have their ophthalmic assessment at these public hospital eye clinics, revealing lengthy 'wait-for-waits' as a barrier to care. Standardized referral templates may facilitate improvement of referral pathways and shorten waiting times.