Electrochemical Oxidative 1,2-Dithiocyanation: Access to Functionalized Alkenes and Alkynes.

Reported herein is the 1,2-dithiocyanation of alkenes and alkynes via an efficient and facile electrochemical method. This approach not only showed a broad substrate scope and good functional-group compatibility but also avoided stoichiometric oxidants. Different from previous reports, various internal alkynes could be tolerated to provide tetra-substituted alkenes. Further gram-scale-up experiments and synthetic transformation demonstrated a potential application in organic synthesis. This process underwent a radical pathway, as evidenced by our mechanistic studies.

Photoinduced Catalyst-Free Deuterodefunctionalization of Aryltriazenes with CDCl3.

A photoinduced deuterodetriazenation of aryltriazenes with CDCl3 under catalyst-free conditions is reported. The reactions featured simple operation, ecofriendly conditions, readily available reagents, inexpensive D sources, precise site selectivity, and a wide range of substrates. Since aryltriazenes could be readily synthesized from arylamine, this protocol can be used as a general method for easily and accurately incorporating deuterium into aromatic systems by using CDCl3 as a D source.

Visible-Light-Promoted and EDA Complex-Driven [4 + 2] Annulation for the Construction of Naphtho[1',2':4,5]imidazo[1,2-a]pyridines.

A green visible-light-promoted and electron donor-acceptor (EDA) complex-driven synthetic strategy for the construction of value-added naphtho[1',2':4,5]imidazo[1,2-a]pyridines from 2-arylimidazo[1,2-a]pyridines with Z-α-bromocinnamaldehydes has been accomplished under photocatalyst- and transition-metal-free conditions. This efficient annulation approach provides a new and straightforward pathway for the annulative π-extension of imidazo[1,2-a]pyridine-based aromatics. Moreover, the sustainable methodology exhibits simple operation, a wide range of substrates, benign conditions, and good functional group compatibility.

ZBP1 promotes hepatocyte pyroptosis in acute liver injury by regulating the PGAM5/ROS pathway.

INTRODUCTION AND OBJECTIVES: Acute liver injury (ALI) is characterized by massive hepatocyte death with high mortality and poor prognosis. Hepatocyte pyroptosis plays a key role in the physiopathological processes of ALI, which can damage mitochondria and release NLRP3 inflammasome particles, causing systemic inflammatory responses. Z-DNA Binding Protein 1 (ZBP1) is a sensor that induces cell death. Here, we investigated whether ZBP1 participates in hepatocyte pyroptosis and explored the possible pathogenesis of ALI. MATERIALS AND METHODS: Hepatocyte pyrotosis was induced with lipopolysaccharide (LPS) and nigericin (Nig), and the expression of Zbp1 (ZBP1) was examined by western blot analysis and RT-qPCR. Further, we transfected AML-12 (LO2 and HepG2) cell lines with Zbp1 (ZBP1) siRNA. After ZBP1 was silenced, LDH release and flow cytometry were used to measure the cell death; Western blot analysis and RT-qPCR were used to detect the marker of NLRP3 inflammasome activation and pyroptosis. We also detected the expression of mitochondrial linear rupture marker phosphoglycerate mutase family member 5 (PGAM5) using western blot analysis and reactive oxygen species (ROS) using the DCFH-DA method. RESULTS: The expression of ZBP1 was up-regulated in LPS/Nig-induced hepatocytes. Si-Zbp1 (Si-ZBP1) inhibited NLRP3 inflammasome activation and pyroptosis in LPS/Nig-induced hepatocytes. Moreover, ZBP1 silencing inhibited the expression of PGAM5 by reducing ROS production. CONCLUSIONS: ZBP1 promotes hepatocellular pyroptosis by modulating mitochondrial damage, which facilitates the extracellular release of ROS.

Pd-Catalyzed Direct C7 Trifluoromethylation of Indolines with Umemoto's Reagent.

An efficient palladium-catalyzed region-selective C7-trifluoromethylation of indolines using commercially available Umemoto's reagent was reported. The reaction utilizing Umemoto's reagent as CF3 radical precursor, pyrimidine as a removable directing group, Pd(II) as a catalyst, and Cu(II) as an oxidant furnished the required products with excellent regioselectivities and good yields. The present strategy has good region-selectivity, broad substrate scope, and scale-up application. Additionally, the present method was underlined by the direct C-1 trifluoromethylation of carbazoles. Furthermore, C7 trifluoromethylated indole can also be easily obtained via Pd-catalyzed direct C-7 trifluoromethylation/oxidation/deprotection sequential reactions.

Incidence and predictors of elevated postpartum alanine aminotransferase in chronic hepatitis B mothers: a prospective study protocol.

BACKGROUND: The majority of HBeAg-positive mothers with chronic hepatitis B have high levels of viremia and inactive disease with normal alanine aminotransferase (ALT) during pregnancy. In addition, postpartum disease activation and ALT flare have been reported in the range of 15 - 35%. However, the current International Association Guidelines have not provided clear recommendations and a risk-stratified monitoring schedule. Furthermore, data are lacking on the definition of normal ALT in the postpartum period in mothers with chronic hepatitis B. The clinical features and ALT flare patterns in HBeAg-positive mothers versus HBeAg-negative mothers are not fully explored. Thus, we design a cohort study to investigate the aforementioned area and generate data to assist healthcare providers in better managing mothers with hepatitis B. We aim to assess the frequency of postpartum ALT flares and predictors for such events. METHOD: This study is a single-center and prospective cohort study (n = 360) that consists of two groups of patients including HBsAg-positive mothers (n = 120) and healthy mothers without HBV infection (n = 240). In HBeAg-positive mothers, antiviral therapy during late pregnancy is permitted to prevent Mother-to-child transmission (MTCT) but discontinued at delivery if there is no further indication for the treatment. Mothers are enrolled at the gestational weeks of 12-24. After delivery, both mothers and their infants will be followed up until postpartum week 24. Clinical and laboratory data are collected every 4 weeks during the study except there are no follow-up visits at the postpartum weeks 16 and 20. The primary objective is the proportion of patients with postpartum ALT flares. The secondary objectives are independent risk factors during pregnancy for predicting postpartum ALT flares and the normal range of postpartum ALT levels in healthy mothers. DISCUSSION: The current study focuses on the incidence of postpartum ALT flares in mothers with chronic hepatitis B including subgroup analysis based on HBeAg status. The data will have several clinical implications, such as providing evidence for an appropriate monitoring schedule in CHB mothers after delivery. Further analyses on predictors of such events may assist clinicians in identifying mothers who might develop severe postpartum ALT flares. The data generated from healthy mothers have the potential to identify the patterns of ALT changes during pregnancy and postpartum, so we can gain a better understanding of the normal range of ALT in this subpopulation. TRIAL REGISTRATION NUMBER AT THE CHINESE CLINICAL TRIAL REGISTRY: ChiCTR2200061130.

Concurrent chronic myelomonocytic leukemia and gastric carcinoma: a case report and literature review.

Background: Chronic myelomonocytic leukemia (CMML) is a rare, malignant, clonal hematopoietic disorder with features of both myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). It is classified as MDS/MPN overlap syndrome by the World Health Organization (WHO), and the prognosis is generally poor. Solid tumors are rarely associated with or are secondary to CMML. Case Description: We here reported a case of a 75-year-old female patient with persistent peripheral blood monocytosis and bone marrow blasts ≤20%. A diagnosis of CMML was made. Unexpectedly, she presented with recurrent melena and red blood cell (RBC) transfusions were ineffective. Capsule endoscopy revealed gastric space-occupying lesions, and pathological biopsy confirmed gastric adenocarcinoma. Because of the patient's history of coronary heart disease and the fact that she underwent percutaneous coronary intervention with stenting less than half a year ago, the diagnosis and treatment of this patient required a multidisciplinary team of hematologists, oncologists, anesthesiologists and cardiologists. Conclusions: Physicians should consider the possibility of other malignant solid tumors in patients with CMML. For patients at high risk for gastrointestinal endoscopy, capsule endoscopy may be a safer way to determine if a patient needs further endoscopic biopsy. There are currently no guidelines for the treatment of CMML with gastric cancer.

Vulvar squamous intraepithelial neoplasia epithelial thickness in hairy and non-hairy sites: a single center experience from China.

Introduction: A large-sample study focusing on VIN lesions of a more precise thickness is needed to help guide clinical treatment. This study aimed to investigate the depth of vulvar intraepithelial neoplasia (VIN) and involved skin appendages to provide evidence for laser surgery. Methods: The study retrospectively enrolled and analyzed the clinical characteristics of VIN patients in the obstetrics and gynecology department of a university hospital between January 1, 2019 and December 30, 2021. The study further explored the thickness of epithelium and skin appendages of 285 women with low-grade VIN (VIN1) and 285 women with high-grade VIN (VIN2/3). Results: The study included 1,139 (80%) VIN1 and 335 (20%) VIN2/3 cases. The VIN1 and VIN2/3 groups showed a significant difference in human papillomavirus infection (P<0.01) but not in cytology (P = 0.499). Most (89.90%, 1,325) cases occurred in one area of the vulva, whereas 10.11% were multifocal. VIN commonly occurred on the posterior fourchette (76.85%), labia majora (11.61%), and labia minora (9.92%). The VIN2/3 group reported a significantly higher positive rate for concurrent cervical and vaginal intraepithelial neoplasia (160 of 285) than the VIN1 group (321 of 953) (P=0.000). The involved epithelial thicknesses in VIN2/3 and VIN1 were 0.69 ± 0.44 and 0.49 ± 0.23 mm, respectively, both of which were greater than the corresponding noninvolved epithelial thickness (0.31 ± 0.19 and 0.32 ± 0.10 mm, P<0.001 and P<0.001, respectively). In cases of appendage involvement, the VIN thickness was 1.98 ± 0.64 mm. Conclusions: VIN thickness was generally ≤1 mm for the superficial lesions in non-hairy areas. However, for lesions extending onto hairy areas, the thickness was approximately 3 mm, leading to the destruction of involved skin appendages.

Three cases of scrub typhus with hemorrhage: a case report and literature review.

Scrub typhus (ST) is an acute focal infectious disease that is caused by Orientia tsutsugamushi. The Asia-Pacific region is an area of relatively high incidence. There is a high incidence in China, principally owing to the disease being endemic in the south of the country. The main source of ST infection is rats, which act as reservoirs of infection after being bitten by the chigger mite, and the human population is generally susceptible to the disease. ST can be controlled and treated successfully if antibiotics are administered in a timely manner. However, because it does not have a specific clinical manifestation, it is difficult to distinguish ST from other febrile diseases in clinical practice. Therefore, rapid diagnostic methods are still needed to help clinicians make a timely diagnosis. Here, we share three cases of patients with ST who experienced hemorrhage, but did not have typical skin lesions, such as eschar and ulcer, early in the course of their disease, and review the relevant literature regarding ST. We conclude that clinicians should pay attention to the risk of hemorrhage associated with this disease, and emphasize the importance of making an early diagnosis.

Value of loop electrosurgical excision procedure conization and imaging for the diagnosis of papillary squamous cell carcinoma of the cervix.

Background: Loop electrosurgical excision procedure (LEEP) conization and hysterectomy are performed for some patients with papillary squamous cell carcinoma (PSCC), whereas only hysterectomy is performed for others. We aimed to determine the optimal management for PSCC. Methods: Patients diagnosed with PSCC by colposcopy-directed biopsy between June 2008 and January 2020 who underwent LEEP conization and hysterectomy or only hysterectomy at our hospital were enrolled. Results of cervical cytology, high-risk human papillomavirus testing, transvaginal sonography, pelvic magnetic resonance imaging, LEEP, hysterectomy, and pathology testing of colposcopy-directed biopsy samples were analyzed. Results: A total of 379 women were diagnosed with PSCC by colposcopy-directed biopsy; 174 underwent LEEP before hysterectomy and 205 underwent only hysterectomy. Patients underwent and did not undergo LEEP were aged 47 ± 11 years and 52 ± 11 years, respectively. Among women who underwent LEEP, the agreement between LEEP and hysterectomy pathology was 85.1%. For women who underwent only hysterectomy, the agreement between preoperative clinical staging and pathological staging after hysterectomy was 82.4%. For patients with preoperative imaging indicative of malignancy, the accuracy of LEEP for diagnosing and staging PSCC was 88.5%, whereas for the hysterectomy-only group, it was 86.2%. For patients without malignancy detected with imaging, the accuracy of LEEP for diagnosing and staging PSCC was 81.6%; however, for those who did not undergo LEEP, it was 70.0%. Conclusion: For women diagnosed with PSCC by colposcopy-directed biopsy, LEEP conization is necessary for an accurate diagnosis when imaging does not indicate cancer; however, LEEP is not necessary when imaging indicates cancer.

Data driven time-varying SEIR-LSTM/GRU algorithms to track the spread of COVID-19.

COVID-19 is an infectious disease caused by a newly discovered coronavirus, which has become a worldwide pandemic greatly impacting our daily life and work. A large number of mathematical models, including the susceptible-exposed-infected-removed (SEIR) model and deep learning methods, such as long-short-term-memory (LSTM) and gated recurrent units (GRU)-based methods, have been employed for the analysis and prediction of the COVID-19 outbreak. This paper describes a SEIR-LSTM/GRU algorithm with time-varying parameters that can predict the number of active cases and removed cases in the US. Time-varying reproductive numbers that can illustrate the progress of the epidemic are also produced via this process. The investigation is based on the active cases and total cases data for the USA, as collected from the website "Worldometer". The root mean square error, mean absolute percentage error and r2 score were utilized to assess the model's accuracy.

Visible-Light-Promoted [3 + 2] Cyclization of Chalcones with 2-Mercaptobenzimidazoles: A Protocol for the Synthesis of Imidazo[2,1-b]thiazoles.

A visible-light-promoted [3 + 2] cyclization between chalcones and 2-mercaptobenzoimidazoles for the construction of diverse imidazo[2,1-b]thiazoles via an electron-donor-acceptor (EDA) complex has been developed. This novel aminothiolation can be realized under only visible light irradiation without the aid of external photocatalysts, transition metals, and oxidants. Mechanistic investigations have revealed that the thiol anions and chalcones form EDA complexes, providing a novel strategy for the synthesis of imidazo[2,1-b]thiazoles.

SEIR model with unreported infected population and dynamic parameters for the spread of COVID-19.

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be transmitted through human interaction. In this paper, we present a Piecewise Susceptible-Exposed-Infectious-Unreported-Removed model for infectious diseases and discuss qualitatively and quantitatively. The parameters are explored by mathematical and statistical methods. Numerical simulations of these models are performed on COVID-19 US data and Python is used in the visualization of results. Outbreak factor is generated by piecewise model to explore the future trend of the US pandemic. Several error metrics are given to discuss the accuracy of the models. The main achievement of this paper is to propose the piecewise model and find the relationship between spread of pandemic and mitigation measures to control it by observing the results of numerical simulations. Performance analysis of piecewise model is presented based on COVID-19 data obtained by 'worldmeter'.

Lenalidomide improves the antitumor activity of CAR-T cells directed toward the intracellular Wilms Tumor 1 antigen.

OBJECTIVES: CAR-based immunotherapies represent a potentially curative strategy for hematological malignancies. However, there are a number of intracellular antigens that CAR-T cells are unable to target. Furthermore, CAR-T cells often suffer from insufficient expansion in part because of the immunosuppressive mechanisms. Lenalidomide (LEN), an immunomodulatory drug, can potentiate T cell functionality. Therefore, it is necessary to investigate combinatorial therapy using CAR-T cells and LEN for enhancing function. METHODS: We redirected T cells to express HLA-A*2402+-restricted-CAR capable of recognizing WT1235-243 peptide and adoptively transferred them into tumor-bearing mice to test their anti-tumor activity. Then we assessed the combinatorial efficacy using CAR-T cells and LEN in vitro and in vivo. RESULTS: Using an anti-WT1 CAR-T, we showed that LEN enhances CAR-T cell function in a concentration-dependent manner. Our data demonstrated that LEN improved the anti-tumor activity of CAR-T cells in vivo by increasing the infiltration of tumors with CD3+ and CD8+ T cells. Proteomics studies supported LEN enhanced the efficacy of CAR-T cells, including T-cell activation, mitochondrial activity and immune synapse formation. CONCLUSION: These results demonstrate that lenalidomide potentiates WT1 CAR-T activity and paves the way to evaluate the combination of LEN with CAR-T for a planned clinical trial.

Inhibition of hsa_circ_0003489 shifts balance from autophagy to apoptosis and sensitizes multiple myeloma cells to bortezomib via miR-874-3p/HDAC1 axis.

BACKGROUND: Circular RNAs (circRNAs) crucially regulate tumor progression. In this study, we examined the functional roles and mechanisms of hsa_circ_0003489 in multiple myeloma (MM). METHODS: Upon altering the expressions of hsa_circ_0003489, miR-874-3p, and/or histone deacetylase 1 (HDAC1) in MM1.R cells and treating them with bortezomib (BTZ), cell viability was examined by CCK-8 assay; cell proliferation by Ki-67 immunofluorescence; apoptosis by TUNEL staining, flow cytometry, and western blot; and autophagy by electron microscopy and western blot. The interaction between hsa_circ_0003489 and miR-874-3p as well as that between miR-874-3p and HDAC1 was examined by expressional analysis, dual luciferase reporter assay, and RNA immunoprecipitation. The in vivo impacts of hsa_circ_0003489 on MM growth and sensitivity to BTZ were examined using an MM xenograft mouse model. RESULTS: Knocking down hsa_circ_0003489 significantly inhibited the viability, cell proliferation, and autophagy, while promoting the apoptosis of MM cells in vitro and MM xenograft in vivo. Suppressing hsa_circ_0003489 also further boosted the cytotoxic effects of BTZ in MM cells and reversed its promoting effect on autophagy. Mechanically, hsa_circ_0003489 acted as a sponge of miR-874-3p and positively regulated the expression of miR-874-3p target, HDAC1. MiR-874-3p and HDAC1 essentially mediated the effects of hsa_circ_0003489 on cell viability, proliferation, apoptosis, and autophagy. CONCLUSION: The hsa_circ_0003489/miR-874-3p/HDAC1 axis critically regulates the balance between apoptosis and autophagy. Silencing hsa_circ_0003489 sensitizes MM cells to BTZ by inhibiting autophagy and thus may boost the therapeutic effects of BTZ.

Aminothiolation of α-Bromocinnamaldehydes to Access Imidazo[2,1-b]thiazoles by Incorporation of Two Distinct Photoinduced Processes.

A visible-light-promoted metal-free catalytic system was developed to achieve the aminothiolation of α-bromocinnamaldehydes. This mechanistically novel approach allows the synthesis of diverse imidazo[2,1-b]thiazole derivatives in satisfactory yields at room temperature under visible-light irradiation by incorporation of two distinct photoinduced processes. The reaction features readily accessible feedstocks, easy operation, mild reaction conditions, and wide reaction scope.

Microbial antigens-loaded myeloma cells enhance Th2 cell proliferation and myeloma clonogenicity via Th2-myeloma cell interaction.

BACKGROUND: Myeloma cells retain B cell functions, considered to be potential antigen presenting cells, yet there is little information regarding promoting Th2 cell proliferation or the direct effects to myeloma on the Th2 cells stimulated by microbial antigens-loaded myeloma cells. METHODS: Mixed lymphocyte reaction was used colorimetric assays via CCK8-kit. Surface molecular expression was performed by flow cytometry, cells sorting using microbeads. The concentrations of cytokines in serum were assessed using an ELISA kit. Clonogenic assay were performed in a methylcellulose culture system. Statistical analysis was assessed using the Student's t-test or one-way analysis of variance for multiple comparisons test. RESULTS: The expression of HLA-DR, CD80 and CD40 on RPMI8266 cell membrane surface was upregulated by interaction with interferon-γ and/or Bacillus Calmette-Guerin Vaccine (BCGV). RPMI8266 cells were able to induce the mixed lymphocyte reaction in a dose-dependent fashion. The Th2 ratio induced by RPMI8266 treated by BCGV and interferon-γ (treated-RPMI8266) cells was only slightly greater than by untreated-tumor cells, but the serum IL-4 level secreted by Th2 cells was markedly higher in treated-RPMI8266 cells group. Th2 cells stimulated by treated-myeloma cells could directly promote treated-myeloma cell clonogenicity in a dose-dependent manner. Anti-HLADR IgG2b completely blocked increased of IL-4 secretion by Th2 cells stimulated by treated-myeloma cells, while also blocked enhancing the clonogenicity of treated tumor cells stimulated by MM-Th2 cells. CONCLUSIONS: These results indicate that a novel mechanism of myeloma pathogenesis in myeloma cells could act as an APC to present microbial Ags to Th2 cells, promoting Th2 cell proliferation, consequently facilitating tumor development by close interaction between Th2 myeloma cells. Taken together, the microbial Ag presenting course of MM-Th2-MM interactions-restricted by MHC class-II-may result in tumor development such that all factors involved in the system could have a potential for myeloma therapeutic intervention.

The epidemiological trend of acute promyelocytic leukemia over past four decades: a population-based analysis.

The treatment regimens for acute promyelocytic leukemia (APL) dramatically changed over time. However, its survival trend, based on a large sample size has not been reported. Patients diagnosed with APL were accessed from the Surveillance, Epidemiology, and End Results database. Their incidence and survival trend were evaluated in overall and subgroup levels. The overall incidence of APL increased with an annual percentage change of 5.5% from 1992 to 2006 and remained stable thereafter. In addition, the 5-year relative survival rates of APL improved significantly, from 12.3 to 32.2% to 59.5 to 72.1% over past four decades (p < .0001), sharing similar trend with different subgroups. Importantly, survival disparities exist among races and different socioeconomic status groups, with superior survival in whites and patients in low-poverty regions. Increasing incidence urges for increased awareness of clinicians over diagnosis of APL. In addition, a wider insurance coverage may help balance survival gap.