COVID-19 acts like a stress test, uncovering the vulnerable part of the human body: a retrospective study of 1640 cases in China.

BACKGROUND: Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection exhibits multi-organ damage with diverse complications, the correlation between age, gender, medical history and clinical manifestations of novel coronavirus disease 2019 (COVID-19) patients was investigated. METHODS: 1640 patients who were infected with SARS-CoV-2 and hospitalized at the First Affiliated Hospital of Ningbo University from 22 December 2022 to 1 March 2023 were categorized and analysed. Normal distribution test and variance homogeneity test were performed. Based on the test results, one-way analysis of variance, Pearson's chi-squared test and logistic regression analysis were conducted in the study. RESULTS: According to the ANOVA, there was a significant difference in the age distribution (P = .001) between different clinical presentations, while gender did not (P = .06). And regression analysis showed that age, hypertension, atherosclerosis and cancer were significant hazard factors for the development of predominant clinical manifestations in patients hospitalized with novel COVID-19. Additionally, infection with SARS-CoV-2 has the potential to exacerbate the burden on specific diseased or related organs. CONCLUSION: The elderly who are infected with SARS-CoV-2 ought to be treated with emphasis not only on antiviral therapy but also on individualized treatment that takes their medical history and comorbidities into account.

The role of lysine-specific demethylase 6A (KDM6A) in tumorigenesis and its therapeutic potentials in cancer therapy.

Histone demethylation is a key post-translational modification of chromatin, and its dysregulation affects a wide array of nuclear activities including the maintenance of genome integrity, transcriptional regulation, and epigenetic inheritance. Lysine specific demethylase 6A (KDM6A, also known as UTX) is an Fe2+- and α-ketoglutarate- dependent oxidase which belongs to KDM6 Jumonji histone demethylase subfamily, and it can remove mono-, di- and tri-methyl groups from methylated lysine 27 of histone H3 (H3K27me1/2/3). Mounting studies indicate that KDM6A is responsible for driving multiple human diseases, particularly cancers and pharmacological inhibition of KDM6A is an effective strategy to treat varieties of KDM6A-amplified cancers in cellulo and in vivo. Although there are several reviews on the roles of KDM6 subfamily in cancer development and therapy, all of them only simply introduce the roles of KDM6A in cancer without systematically summarizing the specific mechanisms of KDM6A in tumorigenesis, which greatly limits the advances on the understanding of roles KDM6A in varieties of cancers, discovering targeting selective KDM6A inhibitors, and exploring the adaptive profiles of KDM6A antagonists. Herein, we present the structure and functions of KDM6A, simply outline the functions of KDM6A in homeostasis and non-cancer diseases, summarize the role of KDM6A and its distinct target genes/ligand proteins in development of varieties of cancers, systematically classify KDM6A inhibitors, sum up the difficulties encountered in the research of KDM6A and the discovery of related drugs, and provide the corresponding solutions, which will contribute to understanding the roles of KDM6A in carcinogenesis and advancing the progression of KDM6A as a drug target in cancer therapy.

Precatalyst-Enabled Selectivity: Enantioselective NiH-Catalyzed anti-Hydrometalative Cyclization of Alkynones to Endo- and Heterocyclic Allylic Alcohols.

A highly enantioselective NiH-catalyzed hydrocyclization of alkynones with unparalleled anti- and endocyclic selectivities is described. The choice of the precatalysts has significant influence in tuning the regio- and enantioselectivity. Using Ni(OTs)2 /Phox as a precatalyst and (EtO)2 MeSiH as a hydride source, an array of enantioenriched O-, N-, and S-containing heterocyclic tertiary allylic alcohols are obtained in 24-81 % yields with 80:20-99:1 er. Mechanistic investigations and synthetic application are also carried out. This study represents an efficient access to a set of allylic alcohols that are unable to access by the state-of-the-art coupling reactions.

Novel D-A-D-Type Supramolecular Aggregates with High Photoelectric Activity for Construction of Ultrasensitive Photoelectrochemical Biosensor.

In this work, hydrazine-functionalized perylene diimide derivative supramolecular (HPDS), a novel self-enhanced donor-acceptor-donor (D-A-D) type aggregates with excellent photoelectric activity, was synthesized by a facile one-pot green route and further applied in construction of coreactant-free photoelectrochemical (PEC) biosensor for ultrasensitive DNA assay. Impressively, the HPDS formed by D-A-D units not only possessed effectively shorted electron-transfer path between donor and acceptor, but also presented a desiring aggregate state via the π-π stacking of perylene core and hydrogen bonding of the terminal moiety, thereby acquiring a high density electron flow for generating the extremely high PEC signal. Experimental data showed that the well film-formed HPDS aggregate could produce an exciting photocurrent intensity about 6-fold stronger than that of precursor perylene dianhydride with donor N2H4 in detection buffer and even 12-fold than that of perylene dianhydride only. In this respect, the resultant HPDS aggregate as a novel self-enhanced PEC signal tag was adopted to fabricate the coreactant-free PEC biosensor with the help of target dual-recycling-induced bipedal DNA walker cascade amplification strategy for ultrasensitive DNA (a fragment of TP53 gene) assay. The proposed biosensor showed a high sensitivity with a low detection limit down to femtomole level, providing a new avenue for sensitive bioanalysis and clinical diagnosis.

General and Practical Potassium Methoxide/Disilane-Mediated Dehalogenative Deuteration of (Hetero)Arylhalides.

Herein we describe a general, mild and scalable method for deuterium incorporation by potassium methoxide/hexamethyldisilane-mediated dehalogenation of arylhalides. With CD3CN as a deuterium source, a wide array of heteroarenes prevalent in pharmaceuticals and bearing diverse functional groups are labeled with excellent deuterium incorporation (>60 examples). The ipso-selectivity of this method provides precise access to libraries of deuterated indoles and quinolines. The synthetic utility of our method has been demonstrated by the incorporation of deuterium into complex natural and drug-like compounds.

Diagnostic value of surfactant protein-a in severe acute pancreatitis-induced acute respiratory distress syndrome.

BACKGROUND: The complexity of multiple-item criteria in acute respiratory distress syndrome (ARDS) often causes inconvenience for physicians in the management of patients with severe acute pancreatitis (SAP). We evaluated whether serum SP-A levels in the presence of diffuse alveolar damage (DAD) can be qualitatively assessed for diagnosis of SAP-induced ARDS. MATERIAL AND METHODS: Eighty rats were randomly divided into 2 groups (n=40 each) - the sham-operated (SO) group and the SAP group - and then randomly subdivided into 4 subgroups in a time-course manner. Furthermore, rats in the SAP group were subdivided into the SAP induced-ARDS group (ARDS group) and the SAP without ARDS group (non-ARDS group) according to the diagnostic standard of ARDS. The diagnostic cut-off values of SP-A for SAP-induced ARDS were determined by the receiver operating characteristic curve (ROC). RESULTS: Serum SP-A levels in Baseline, SO group, SAP group, ARDS group, and non-ARDS group were 43.15±14.29, 51.91±16.99, 193.4±35.37, 198.0+29.73, and 185.7±43.21 ug/ml, respectively. The best cut-off value for the serum SP-A level for the diagnosis of SAP-induced ARDS was 150 ug/ml and the area under the ROC curve of SP-A was 0.88. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of SP-A in the diagnosis of SAP-induced ARDS were 100.0%, 81.8%, 71.4%, 100.0%, and 87.5%, respectively. CONCLUSIONS: Serum SP-A levels may allow the detection of SAP-induced ARDS and may help to support the clinical diagnosis of ARDS. The optimal serum SP-A cut-off value to discriminate SAP-induced ARDS and other groups (SO group and non-ARDS group) is around 150 ug/ml.

Effectiveness of thymectomy in non-thymomatous myasthenia gravis: a systematic review.

There is continuous debate regarding the effectiveness of thymectomy in the treatment of non-thymomatous myasthenia gravis (MG). This systematic review was undertaken to determine whether thymectomy was effective in non-thymomatous MG. We retrieved articles published between January 1980 and September 2013. Sixteen cohort studies were included. Given the considerable heterogeneity, we used a descriptive method instead of statistical synthesis. The median relative rates (RRs) and their interquartile ranges were used to estimate the magnitude of benefit. Compared to conservatively treated MG patients, thymectomized patients had higher survival, clinical remission, pharmacologic remission and improvement rates, and RRs were 1.07 (1.01-1.17), 1.83 (0.82-2.99), 1.55 (1.22-1.95) and 1 (1.00-1.09), respectively. Subgroup analyses showed that patients with moderate to severe generalized MG benefited more from thymectomy, with RRs of survival and pharmacologic remission increasing to 1.35 (1.24-1.49) and 2.68 (1.73-4.17), respectively. These results suggested that thymectomy might be an effective procedure in non-thymomatous MG patients. The patients with moderate to severe generalized MG might benefit more. Taking into account the poor methodological quality of present studies, more well-designed prospective randomized controlled trials (RCTs) are still required to reach unequivocal conclusion.

The emerging roles of leukocyte cell-derived chemotaxin-2 in immune diseases: From mechanisms to therapeutic potential.

Leukocyte cell-derived chemotaxin-2 (LECT2, also named ChM-II), initially identified as a chemokine mediating neutrophil migration, is a multifunctional secreted factor involved in diverse physiological and pathological processes. The high sequence similarity of LECT2 among different vertebrates makes it possible to explore its functions by using comparative biology. LECT2 is associated with many immune processes and immune-related diseases via its binding to cell surface receptors such as CD209a, Tie1, and Met in various cell types. In addition, the misfolding LECT2 leads to the amyloidosis of several crucial tissues (kidney, liver, and lung, etc.) by inducing the formation of insoluble fibrils. However, the mechanisms of LECT2-mediated diverse immune pathogenic conditions in various tissues remain to be fully elucidated due to the functional and signaling heterogeneity. Here, we provide a comprehensive summary of the structure, the "double-edged sword" function, and the extensive signaling pathways of LECT2 in immune diseases, as well as the potential applications of LECT2 in therapeutic interventions in preclinical or clinical trials. This review provides an integrated perspective on the current understanding of how LECT2 is associated with immune diseases, with the aim of facilitating the development of drugs or probes against LECT2 for the theranostics of immune-related diseases.

Estimated pulse wave velocity is associated with all-cause mortality and cardiovascular mortality among adults with diabetes.

Aims: We aim to examine the association of estimated pulse wave velocity (ePWV) with all-cause and cardiovascular mortality in patients with diabetes. Methods: All of adult participants with diabetes from the National Health and Nutrition Examination Survey (NHANES) (1999-2018) were enrolled. ePWV was calculated according to the previously published equation based on age and mean blood pressure. The mortality information was obtained from the National Death Index database. Weighted Kaplan-Meier (KM) plot and weighted multivariable Cox regression was used to investigate the association of ePWV with all-cause and cardiovascular mortality risks. Restricted cubic spline was adopted to visualize the relationship between ePWV and mortality risks. Results: 8,916 participants with diabetes were included in this study and the median follow-up duration was ten years. The mean age of study population was 59.0 ± 11.6 years, 51.3% of the participants were male, representing 27.4 million patients with diabetes in weighted analysis. The increment of ePWV was closely associated with increased risks of all-cause mortality (HR: 1.46, 95% CI: 1.42-1.51) and cardiovascular mortality (HR: 1.59, 95% CI: 1.50-1.68). After adjusting for cofounding factors, for every 1 m/s increase in ePWV, there was a 43% increased risk of all-cause mortality (HR: 1.43, 95% CI: 1.38-1.47) and 58% increased of cardiovascular mortality (HR: 1.58, 95% CI: 1.50-1.68). ePWV had positive linear associations with all-cause and cardiovascular mortality. KM plots also showed that the risks of all-cause and cardiovascular mortality were significantly elevated in patients with higher ePWV. Conclusions: ePWV had a close association with all-cause and cardiovascular mortality risks in patients with diabetes.

A state-of-the-art review on LSD1 and its inhibitors in breast cancer: Molecular mechanisms and therapeutic significance.

Breast cancer (BC) is a kind of malignant cancer in women, and it has become the most diagnosed cancer worldwide since 2020. Histone methylation is a common biological epigenetic modification mediating varieties of physiological and pathological processes. Lysine-specific demethylase 1 (LSD1), a first identified histone demethylase, mediates the removal of methyl groups from histones H3K4me1/2 and H3K9me1/2 and plays a crucial role in varieties of cancer progression. It is also specifically amplified in breast cancer and contributes to BC tumorigenesis and drug resistance via both demethylase and non-demethylase manners. This review will provide insight into the overview structure of LSD1, summarize its action mechanisms in BC, describe the therapeutic potential of LSD1 inhibitors in BC, and prospect the current opportunities and challenges of targeting LSD1 for BC therapy.

Berberine as a potential agent for breast cancer therapy.

Breast cancer (BC) is a common malignancy that mainly occurred in women and it has become the most diagnosed cancer annually since 2020. Berberine (BBR), an alkaloid extracted from the Berberidacea family, has been found with broad pharmacological bioactivities including anti-inflammatory, anti-diabetic, anti-hypertensive, anti-obesity, antidepressant, and anticancer effects. Mounting evidence shows that BBR is a safe and effective agent with good anticancer activity against BC. However, its detailed underlying mechanism in BC treatment remains unclear. Here, we will provide the evidence for BBR in BC therapy and summarize its potential mechanisms. This review briefly introduces the source, metabolism, and biological function of BBR and emphasizes the therapeutic effects of BBR against BC via directly interacting with effector proteins, transcriptional regulatory elements, miRNA, and several BBR-mediated signaling pathways. Moreover, the novel BBR-based therapeutic strategies against BC improve biocompatibility and water solubility, and the efficacies of BBR are also briefly discussed. Finally, the status of BBR in BC treatment and future research directions is also prospected.

Disturbed tooth germ development in the absence of MINT in the cultured mouse mandibular explants.

The Msx2-interacting nuclear target protein (MINT) is a nuclear matrix protein that regulates the development of many tissues. However, little is known regarding the role of MINT in tooth development. In this study, we prepared polyclonal antibodies against MINT, and found that that MINT was expressed in different cells at each stage of tooth germ development by immunohistochemistry. The role of MINT in tooth development was further illustrated by the misshapen and severely hypoplastic tooth organ in the cultured mandibular explants of MINT deficient mice. From the initiation to cap stage, the differences between mutants and wild-type molars were more and more distinguished histologically. In the MINT-deficient mandibular explants, the tooth germ was reduced in the overall size and lacked enamel knot, with abnormal dental lamina and collapsed stellate reticulum. Furthermore, the BrdU incorporation experiment showed that the proliferation activity was significantly reduced in MINT-deficient dental epithelium. Our results suggest that MINT plays an important role in tooth development, in particular, epithelial morphogenesis.

[Clinical and angiographic characteristics of patients with slow coronary flow].

OBJECTIVE: To analyze the clinical and angiographic characteristics of patients with slow coronary flow (SCF). METHODS: In this retrospective study, 140 patients with SCF and 140 control subjects without SCF were included. SCF were diagnosed by the combination of TIMI flow grade method and TIMI frame count method. All subjects had angiographically normal coronary arteries. The clinical and laboratory data were obtained from medical records at admission. RESULTS: Compared to control group, patients with SCF were younger [(57.8 +/- 10.7) years vs. (59.8 +/- 8.2) years], rate of smokers (59.3% vs. 46.4%) and diabetes mellitus (49.3% vs. 30.7%), fasting blood glucose (FBG) level [(7.8 +/- 2.8) mmol/L vs. (6.2 +/- 2.0) mmol/L, P < 0.05] and triglyceride (TG) level [(2.11 +/- 1.93) mmol/L vs. (1.67 +/- 1.01) mmol/L, P < 0.05] were higher, while high density lipoprotein cholesterol (HDL-C) level [(1.05 +/- 0.35) mmol/L vs. (1.42 +/- 0.74) mmol/L, P < 0.01] and apolipoprotein A1 (apoA1) level [(1.10 +/- 0.19) mmol/L vs. (1.31 +/- 0.31) mmol/L, P < 0.01] were lower. Among the 140 SCF patients, left anterior descending artery (LAD), left circumflex artery (LCX) and right coronary artery (RCA) were involved at the same time in 92 patients. Among the three vessels, RCA is the most frequent involved vessel (n = 119). After adjusting for other risk factors, current smoking (OR = 1.92, 95% CI: 1.04 - 3.57, P < 0.05), DM history (OR = 2.44, 95% CI:1.32-4.76, P < 0.01), FBG (OR = 2.13, 95% CI:1.16-3.98, P < 0.05), TG (OR = 1.47, 95% CI:1.03-2.13, P < 0.05), HDL-C (OR = 0.47, 95% CI:0.24-0.85, P < 0.05) and apoA1 (OR = 0.55, 95% CI:0.40 - 0.75, P < 0.01) were independent factors for SCF (all P < 0.05). CONCLUSIONS: Our results demonstrated that patients with SCF were prone to have a significant metabolic disorder compared to the control group. Patients with high levels of FBG, TG and low levels of HDL-C were more likely to suffer from SCF, which maybe explained by the development of coronary endothelium and microvascular dysfunction.

Particular tumor of the pancreas: A case report.

BACKGROUND: Granular cell tumor (GCT) of the pancreas is a rare neurogenic tumor. The first case of pancreatic GCT was described in 1975, and up to now, only 7 cases have been reported. CASE SUMMARY: A 53-year-old male had a pancreatic mass for 1 mo. He was not treated at the local hospital, but referred to Henan Tumor Hospital for surgery. Preoperative imaging revealed a 2.0 cm × 2.5 cm-sized mass located in the body of the pancreas. At the microscopic level, a large number of eosinophilic particles are present in the oval tumor cells. The immunohistochemistry of this tumor cell display CD56 (+), blood vessels CD34 (+), Ki-67 (+) < 10%, and S-100 (+). CONCLUSION: GCT of the pancreas should be recognized as a preoperative differential diagnosis of pancreatic tumors. Surgical resection of the tumor should be attempted; however, GCT of the pancreas has a certain rate of tumor metastasis and recurrence. Therefore, GCT of the pancreas requires regular and long-term follow-up.

Pharmacological inhibition of KDM5A for cancer treatment.

Lysine-specific demethylase 5A (KDM5A, also named RBP2 or JARID1A) is a demethylase that can remove methyl groups from histones H3K4me1/2/3. It is aberrantly expressed in many cancers, where it impedes differentiation and contributes to cancer cell proliferation, cell metastasis and invasiveness, drug resistance, and is associated with poor prognosis. Pharmacological inhibition of KDM5A has been reported to significantly attenuate tumor progression in vitro and in vivo in a range of solid tumors and acute myeloid leukemia. This review will present the structural aspects of KDM5A, its role in carcinogenesis, a comparison of currently available approaches for screening KDM5A inhibitors, a classification of KDM5A inhibitors, and its potential as a drug target in cancer therapy.

The emerging role of KDM5A in human cancer.

Histone methylation is a key posttranslational modification of chromatin, and its dysregulation affects a wide array of nuclear activities including the maintenance of genome integrity, transcriptional regulation, and epigenetic inheritance. Variations in the pattern of histone methylation influence both physiological and pathological events. Lysine-specific demethylase 5A (KDM5A, also known as JARID1A or RBP2) is a KDM5 Jumonji histone demethylase subfamily member that erases di- and tri-methyl groups from lysine 4 of histone H3. Emerging studies indicate that KDM5A is responsible for driving multiple human diseases, particularly cancers. In this review, we summarize the roles of KDM5A in human cancers, survey the field of KDM5A inhibitors including their anticancer activity and modes of action, and the current challenges and potential opportunities of this field.

Pd-catalyzed arylation/aza-Michael addition cascade to C2-spiroindolines and azabicyclo[3.2.2]nonanones.

A palladium-catalyzed arylation/aza-Michael addition cascade reaction of ß-substituted cyclic enones and 2-haloanilines has been reported. Using 1 mol% Pd(PPh3)4 as a catalyst, C2-spiroindolines are accessed via an intermolecular vinylogous arylation of ß-alkyl cyclic enones and 2-haloanilines followed by an intramolecular aza-Michael addition. The functional group tolerance of this transformation is examined by 18 examples in up to 93% yield. In the second part, we developed an α'-arylation/aza-Michael addition cascade strategy to construct azabicyclo[3.2.2]nonanones catalyzed by Pd(MeCN)2Cl2·PPh3. This study provides a quick route to complex and useful spiro- and bridged-heterocycles from readily available starting materials in good yields with high regioselectivity.

Silver-promoted regioselective [4+2] annulation reaction of indoles with alkenes to construct dihydropyrimidoindolone scaffolds.

An AgI-promoted regioselective [4+2] annulation reaction of indoles with alkenes has been established. During the transformation, N-centered radicals are generated by the oxidation of the N-H bond of N-alkoxyamides. Control experiments and DFT calculations reveal a plausible mechanism. This synergistic process achieves the direct construction of new C-C and C-N bonds under relatively mild conditions with broad substrate scope, high atom economy, and easy-to-handle nature.

Detosylative (Deutero)alkylation of Indoles and Phenols with (Deutero)alkoxides.

An efficient strategy for N/O-(deutero)alkylation of indoles and phenols with alkoxides/alcohols as the alkylation reagents is described. The consecutive detosylation/alkylation transformations feature mild reaction conditions, high ipso-selectivity, and good functional group tolerance (>50 examples). A one-pot selective N-alkylation of unprotected indoles with alcohols and TsCl is also realized. The application of this method is demonstrated by the introduction of isotope-labeled (CD3 and 13CH3) groups using the readily accessible labeled alcohols and the synthesis of pharmaceuticals.

Construction of Benzofuran-3(2 H)-one Scaffolds with a Quaternary Center via Rh/Co Relay Catalyzed C-H Functionalization/Annulation of N-Aryloxyacetamides and Propiolic Acids.

An unprecedented synthesis of valuable benzofuran-3(2 H)-one scaffolds with a quaternary center was developed via Rh/Co relay catalyzed C-H functionalization/annulation of N-aryloxyacetamides with propiolic acids in moderate to good yields. The reaction features the simultaneous construction of the benzofuran motif containing a C2 quaternary center and a C3 carbonyl group. The preliminary mechanism study verified that the O atom of C3 carbonyl group originates from molecular oxygen.