The Latest Research Progress of Selinexor in the Treatment of Non-Hodgkin Lymphoma --Review / 中国实验血液学杂志

Non-Hodgkin lymphoma (NHL) is a common lymphoid hematological malignancy, the treatment and prognosis of NHL have always been the focus of clinical attention. Chemotherapy is the main first-line treatment, but there is still no effective treatment for patients with poor response to chemotherapy, recurrence or progression within a short period of time after treatment, and new and effective drugs need to be developed clinically. As the only clinically validated oral selective inhibitor of nuclear export (SINE), Selinexor has been approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma and multiple myeloma, clinical attempts are being made to apply it to the treatment of other hematological malignancies.This article reviews the anti-tumor mechanism of Selinexor and the latest research progress in its application in NHL, and provides ideas for a more diverse, standardized and effective applications of Selinexor in NHL.

Assessment of anti-diabetic activity of a novel hydrazine-thiazole derivative: in vitro and in vivo method

Diabetes mellitus is a chronic disease resulting in oxidative stress that promotes tissue damage. The appearance of this disease is highly related to lifestyle and food of the population, being of great interest to search for a dietary supplement that can also act by reducing oxidative alterations. Based on the broad range of biological activity of thiazole derivatives, this work aimed to evaluate the in vitro antioxidant activity of a novel hydrazine-thiazole derivative and studies in vivo. In in vivo experiments, the liver extracts of healthy and diabetic Wistar rats were used, with analysis to determine the enzymatic activity of SOD, CAT, GPx, and GR, and determination of lipid peroxidation. Finally, in the blood of these animals, biochemical parameters were evaluated. Statistical evidence of changes caused in liver enzymes and liquid peroxidation was not detected; however, these parameters were also not changed between control groups with and without diabetes. On the other hand, concerning biochemical parameters, significant differences were detected in uric acid, alkaline phosphatase, ALT, and urea, indicating a possible antioxidant protective role of such substances in the liver and kidney of diabetic animals that could be acting by means other than that commonly reported in the literature.

Trombocitopenia hereditaria relacionada a gen MYH-9: primera familia reportada en Chile con diagnóstico molecular: caso clínico / Hereditary thrombocytopenia associated with a mutation in the MYH-9 gene: report of one case

We report a 51-year-old female who had a first episode of thrombocytopenia at 23 years of age during a pregnancy. At the age of fifty, a hysterectomy was indicated due to a metrorrhagia: a platelet count of 21,000/ul was detected. She was treated with eltrombopag with a good response. The family history of the patient revealed the presence of thrombocytopenia in several family members. Suspecting a hereditary thrombocytopenia, a genetic study revealed a mutation in the MYH-9 gene. This mutation can be suspected when there is a family history of thrombocytopenia with autosomal dominant inheritance, macrothrombocytopenia and in this particular case, due to the response to thrombopoietin receptor agonist, eltrombopag.

Synthesis, pharmacological screening and computational analysis of some 2-[l-Indol-3-yl]-A [[un]substituted phenylmethylidene] acetohydrazides and 2-[l-Indol-3-yl]-7V[[un]substituted benzoyl/2-thienylcarbonyl] acetohydrazides

The undertaken research was initiated by transforming 2-[l-Indol-3-yl]acetic acid [1] in catalytic amount of sulfuric acid and ethanol to ethyl 2-[l-Indol-3-yl]acetate [2], which was then reacted with hydrazine monohydrate in methanol to form 2-[l-Indol-3-yl]acetohydrazide [3]. Further, The reaction scheme was designed into two pathways where, first pathway involved The reaction of 3 with substituted aromatic aldehydes [4a-o] in methanol with few drops of glacial acetic acid to generate 2-[l-Indol-3-yl]-AD-[[un]substitutedphenylmethylidene]acetohydrazides [5a-o] and in second pathway 3 was reacted with acyl halides [6a-e] in basic aqueous medium [pH 9-10] to afford 2-[l-Indol-3-yl]-AD-[[un]substitutedbenzoyl/2-thienylcarbonyl]acetohydrazides [7a-e]. All The synthesized derivatives were characterized by IR, EI-MS and !H-NMR spectral techniques and evaluated for their anti-bacterial potentials against Gram positive and Gram negative bacterial strains and it was found that compounds 7a-d exhibited antibacterial activities very close to standard Ciprofloxacin. The synthesized derivatives demonstrated moderate to weak anti-enzymatic potential against oc-Glucosidase and Butyrylcholinesterase [BChE] where, compounds 7c and 5c exhibited comparatively better inhibition against these enzymes respectively. Compounds 7a, 7d and 7e showed excellent anti-enzymatic potentials against Lipoxygenase [LOX] and their IC[5]o values were much lower than the reference standard Baicalein. Enzyme inhibitory activities were also supported by computational docking results. Compounds 5c, 7a, 7b and 7c also showed low values of % hemolytic activity as well, showing that these molecules were not toxic, indicating that these molecules can be utilized as potential therapeutic agents against inflammatory ailments

Improvement of butanol production by Escherichia coli via Tn5 transposon mediated mutagenesis / 生物工程学报

For engineering an efficient butanol-producing Escherichia coli strain, many efforts have been paid on the known genes or pathways based on current knowledge. However, many genes in the genome could also contribute to butanol production in an unexpected way. In this work, we used Tn5 transposon to construct a mutant library including 1 196 strains in a previously engineered butanol-producing E. coli strain. To screen the strains with improved titer of butanol production, we developed a high-throughput method for pyruvate detection based on dinitrophenylhydrazine reaction using 96-well microplate reader, because pyruvate is the precursor of butanol and its concentration is inversely correlated with butanol in the fermentation broth. Using this method, we successfully screened three mutants with increased butanol titer. The insertion sites of Tn5 transposon was in the ORFs of pykA, tdk, and cadC by inverse PCR and sequencing. These found genes would be efficient targets for further strain improvement. And the genome scanning strategy described here will be helpful for other microbial cell factory construction.

Synthesis and antimycobacterial activity of some triazole derivatives - new route to functionalized triazolopyridazines

A series of cyclic analogues of bioactive thiosemicarbazide derivatives have been synthesized as potential antimycobacterial agents. The 4-amino-1,2,4-triazole-5-thione analogues [Ia-f] were prepared by heating a mixture of thiocarbohydrzide and appropriate carboxylic acids. Reaction of thiocarbohydrazide with gamma-ketoesters in the presence of sodium methoxide furnished triazolopyridazine derivatives IIa-b. Finally, condensation of 4-amino-1,2,4-triazole-5-thione with some aldehydes gave Schiff bases IIIa-e. After characterization by different spectroscopic and analytical methods, the derivatives were tested for their inhibitory activity against Mycobacterium bovis BCG. Among the derivatives, compound Ib proved to be the most potent derivatives with MIC value of 31.25 microg/mL. Given the fact that 4-amino-1,2,4-triazole-5-thiones Ia-f were the most active derivatives, it could be suggested that this group of derivatives have the potential to be considered as lead compounds for future optimization efforts

Impairment of locomotor activity induced by the novel N-acylhydrazone derivatives LASSBio-785 and LASSBio-786 in mice

The N-acylhydrazone (NAH) analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785) and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786) were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294). The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30 mg/kg, ip) reduced locomotor activity from 209 ± 26 (control) to 140 ± 18 (P < 0.05) or 146 ± 15 crossings/min (P < 0.05), respectively. LASSBio-785 (15 or 30 mg/kg, iv) also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05) or 60 ± 16 crossings/min (P < 0.01), respectively. Likewise, LASSBio-786 (15 or 30 mg/kg, iv) reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01) or 96 ± 14 crossings/min (P < 0.01), respectively. Pretreatment with flumazenil (20 mg/kg, ip) prevented the locomotor impairment induced by NAH analogues (15 mg/kg, iv), providing evidence that the benzodiazepine (BDZ) receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30 mg/kg, ip, n = 10) increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO) to 66 ± 6 (P < 0.05) or 75 ± 4 min (P < 0.05), respectively. The dose required to achieve 50% hypnosis (HD50) following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5 mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia.

Multiple Cystic Lung Disease / 결핵및호흡기질환

A lung cyst is an air-filled lucent structure surrounded by a thin wall. The presence of multiple intrapulmonary cysts is defined as cystic lung disease. Although cystic lung disease is rare, incidental detection has increased significantly in recent years by screening using computed tomography. There are many conditions that can mimic lung cysts and cause cystic lung disease. Clinical, radiographic, and histologic findings are all necessary for a proper diagnosis, and multidisciplinary approaches are frequently required. The aim of this report is to review the causes and characteristics of cystic lung disease to better understand and improve treatment.

Effect of the Position of Immobilization Upon the Tensile Properties in Injured Achilles Tendon of Rat

OBJECTIVE: To examine the effect of the posture of immobilization upon the tensile properties in injured Achilles tendon of rat for an initial period of immobilization. METHODS: Forty-two Sprague-Dawley rats were used in the present study. Eighteen rats received a total tenotomy of the right Achilles tendon to mimic total rupture and were divided into three groups comprising of 6 rats each. Ankles of group A were immobilized at 60degrees of plantarflexion. Ankles of group B were immobilized at neutral position. Whereas, those of group C were immobilized at 60degrees of dorsiflexion. Other 18 rats received hemitenotomy to mimic partial rupture and were divided into three groups. The remaining 6 rats were kept free as control. After 14 days, we dissected the tendons and analyzed maximum force, stiffness, and energy uptake during pulling of the tendons until they ruptured. The tendons of 6 rats in each group and control were reserved for histology. Picrosirius staining was done for the analysis of collagen organization. RESULTS: In total tenotomy, tensile properties were significantly different between the control and the intervention groups (p0.05). In partial tenotomy, tensile properties were significantly different between the control and the intervention groups (p<0.05). Group C showed significantly higher value than other intervention groups in terms of maximum force and energy uptake (p<0.05). The semiquantitative histologic grading scores were assigned for collagen organization. The scores for dorsiflexion posture were higher than the ones for plantarflexion. CONCLUSION: Dorsiflexion posture in partial ruptured Achilles tendon showed better functional recovery than other immobilized postures. In total ruptured case, the tensile properties showed increasing tendency in dorsiflexion posture.

PINK1 Deficiency Enhances Inflammatory Cytokine Release from Acutely Prepared Brain Slices

Parkinson's disease (PD) is the second most common neurodegenerative motor disease caused by degeneration of dopaminergic neurons in the substantia nigra. Because brain inflammation has been considered a risk factor for PD, we analyzed whether PTEN induced putative kinase 1 (PINK1), an autosomal recessive familial PD gene, regulates brain inflammation during injury states. Using acutely prepared cortical slices to mimic injury, we analyzed expression of the pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 at the mRNA and protein levels. Both mRNA and protein expression of these cytokines was higher at 6-24 h after slicing in PINK1 knockout (KO) slices compared to that in wild-type (WT) slices. In serial experiments to understand the signaling pathways that increase inflammatory responses in KO slices, we found that IkappaB degradation was enhanced but Akt phosphorylation decreased in KO slices compared to those in WT slices. In further experiments, an inhibitor of PI3K (LY294002) upstream of Akt increased expression of pro-inflammatory cytokines. Taken together, these results suggest that PINK1 deficiency enhance brain inflammation through reduced Akt activation and enhanced IkappaB degradation in response to brain injury.

miR-197 Expression in Peripheral Blood Mononuclear Cells from Hepatitis B Virus-Infected Patients

BACKGROUND/AIMS: This study aimed to investigate the microRNA (miRNA) expression profiles in peripheral blood mononuclear cell (PBMC) of hepatitis B virus (HBV)-infected patients with different clinical manifestations and to analyze the function of miR-197. METHODS: PBMC miRNA expression profiles in 51 healthy controls, 70 chronic asymptomatic carriers, 107 chronic hepatitis B patients, and 76 HBV-related acute on chronic liver failure patients were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). miR-197 mimic and inhibitor were transfected in THP-1 cells. qRT-PCR and ELISA for interleukin (IL)-18 mRNA and protein levels were performed, respectively. RESULTS: The microarray analysis revealed that 17 PBMC miRNA expression profiles (12 miRNAs downregulated and five miRNAs upregulated) differed significantly in HBV-induced liver disease patients presenting with various symptoms. The qRT-PCR results suggested that the PBMC miR-197 levels regularly decreased as the severity of liver disease symptoms became aggravated. IL-18, a key regulator in inflammation and immunity, was inversely correlated with miR-197 levels. Bioinformatic analysis indicated that IL-18 was a target of miR-197. Exogenous expression of miR-197 could significantly repress IL-18 expression at both the mRNA and protein levels in THP-1 cells. CONCLUSIONS: We concluded that multiple PBMC miRNAs had differential expression profiles during HBV infection and that miR-197 may play an important role in the reactivation of liver inflammation by targeting IL-18.

Presumed Ocular Toxoplasmosis Presenting as Isolated Unilateral Papillitis

PURPOSE: To report an atypical case of ocular toxoplasmosis presenting as isolated unilateral papillitis. CASE SUMMARY: A 53-year-old female presented with visual difficulty in her right eye that had begun 1 week previously. Best corrected visual acuity was 0.8 in the right eye and 1.0 in the left eye. On fundoscopic examination, optic disc swelling and focal edema with hard exudates in the nasal parapapillary retina were found in her right eye. Fluorescein angiography revealed marked leakage of dye from the swollen optic disc. There was no evidence of vasculitis and chorioretinitis. Pupillary light reflex and color vision were normal. Visual field (VF) showed generalized reduction in the right eye, and was normal in the left eye. Optical coherence tomography (OCT) revealed right optic disc swelling. Serology was positive for toxoplasma IgM and IgG. The patient was treated with oral steroids and antitoxoplasma antibiotics. Two months later, visual acuity was 1.0 in the right eye. There was no disc swelling on fundoscopy or OCT and VF was normal. CONCLUSIONS: Ocular toxoplasmosis can present atypically as isolated papillitis without chorioretinitis and mimic idiopathic optic neuritis. A thorough serologic examination for toxoplasmosis along with proper treatment should be performed.

A Case of Actinomycosis in a Patient Treated with Chemotherapy Due to Recurrent Pancreatic Cancer / 대한내과학회지

A 46-year-old male patient with recurrent pancreatic cancer was admitted with a newly developed abdominal mass. The patient had a history of diabetes and underwent total pancreatectomy with partial gastrectomy followed by adjuvant concurrent chemoradiation therapy and palliative chemotherapy. Abdominal CT scan during palliative chemotherapy showed an abdominal wall mass. We performed excisional biopsy for diagnosis. Histological examination revealed actinomycosis of the abdominal wall. The patient was treated with penicillin G. This case showed that actinomycosis can occur in a patient receiving chemotherapy and may mimic cancer recurrence. Therefore, when evaluating a newly developed abdominal mass in patients who are receiving chemotherapy or radiotherapy, the probability of actinomycotic infection must also be considered, especially in patients with a history of surgery and diabetes mellitus.

A Case of Actinomycosis in a Patient Treated with Chemotherapy Due to Recurrent Pancreatic Cancer / 대한내과학회지

A 46-year-old male patient with recurrent pancreatic cancer was admitted with a newly developed abdominal mass. The patient had a history of diabetes and underwent total pancreatectomy with partial gastrectomy followed by adjuvant concurrent chemoradiation therapy and palliative chemotherapy. Abdominal CT scan during palliative chemotherapy showed an abdominal wall mass. We performed excisional biopsy for diagnosis. Histological examination revealed actinomycosis of the abdominal wall. The patient was treated with penicillin G. This case showed that actinomycosis can occur in a patient receiving chemotherapy and may mimic cancer recurrence. Therefore, when evaluating a newly developed abdominal mass in patients who are receiving chemotherapy or radiotherapy, the probability of actinomycotic infection must also be considered, especially in patients with a history of surgery and diabetes mellitus.

A Case of Acrometastasis in the Right First Metatarsal Bone Caused by a Metastatic Hepatocellular Carcinoma / 대한내과학회지

Metastases from hepatocellular carcinoma to the bones of the hands or feet are rare. They are usually a late manifestation of a disseminated tumor but may also be the primary manifestation of an occult cancer. Clinically, the metastasis may mimic benign tumors or non-neoplastic osteoarthritic conditions; thus, resulting in misdiagnosis and improper treatment. We report a case of acrometastasis to the right first metatarsal bone in a 70-year-old man with hepatocellular carcinoma.

Mercury Promotes Catecholamines Which Potentiate Mercurial Autoimmunity and Vasodilation: Implications for Inositol 1,4,5-Triphosphate 3-Kinase C Susceptibility in Kawasaki Syndrome

Previously, we reviewed biological evidence that mercury could induce autoimmunity and coronary arterial wall relaxation as observed in Kawasaki syndrome (KS) through its effects on calcium signaling, and that inositol 1,4,5-triphosphate 3-kinase C (ITPKC) susceptibility in KS would predispose patients to mercury by increasing Ca2+ release. Hg2+ sensitizes inositol 1,4,5-triphosphate (IP3) receptors at low doses, which release Ca2+ from intracellular stores in the sarcoplasmic reticulum, resulting in delayed, repetitive calcium influx. ITPKC prevents IP3 from triggering IP3 receptors to release calcium by converting IP3 to inositol 1,3,4,5-tetrakisphosphate. Defective IP3 phosphorylation resulting from reduced genetic expressions of ITPKC in KS would promote IP3, which increases Ca2+ release. Hg2+ increases catecholamine levels through the inhibition of S-adenosylmethionine and subsequently catechol-O-methyltransferase (COMT), while a single nucleotide polymorphism of the COMT gene (rs769224) was recently found to be significantly associated with the development of coronary artery lesions in KS. Accumulation of norepinephrine or epinephrine would potentiate Hg2+-induced calcium influx by increasing IP3 production and increasing the permeability of cardiac sarcolemma to Ca2+. Norepinephrine and epinephrine also promote the secretion of atrial natriuretic peptide, a potent vasodilator that suppresses the release of vasoconstrictors. Elevated catecholamine levels can induce hypertension and tachycardia, while increased arterial pressure and a rapid heart rate would promote arterial vasodilation and subsequent fatal thromboses, particularly in tandem. Genetic risk factors may explain why only a susceptible subset of children develops KS although mercury exposure from methylmercury in fish or thimerosal in pediatric vaccines is nearly ubiquitous. During the infantile acrodynia epidemic, only 1 in 500 children developed acrodynia whereas mercury exposure was very common due to the use of teething powders. This hypothesis mirrors the leading theory for KS in which a widespread infection only induces KS in susceptible children. Acrodynia can mimic the clinical picture of KS, leading to its inclusion in the differential diagnosis for KS. Catecholamine levels are often elevated in acrodynia and may also play a role in KS. We conclude that KS may be the acute febrile form of acrodynia.

Intra-Abdominal Tuberculous Lymphadenitis Diagnosed Using an Endoscopic Ultrasonography-Guided ProCore Needle Biopsy

Intra-abdominal tuberculous lymphadenitis can mimic a variety of other abdominal disorders such as pancreatic cancer, metastatic lymph nodes, or lymphoma, which can make a proper diagnosis difficult. A correct diagnosis of intra-abdominal tuberculous lymphadenitis can lead to appropriate management. Endoscopic ultrasonography (EUS)-guided needle biopsy may be the procedure of choice for tissue acquisition when onsite cytopathology examination is unavailable because it is essential to obtain sufficient material suitable for the examination using an ancillary method, such as flow cytometry, molecular diagnosis, cytogenetics, or microbiological culture. We report a case of intra-abdominal tuberculous lymphadenitis diagnosed using an EUS-guided, 22-gauge histology new needle biopsy without an onsite cytopathology examination.

A Case of Q Fever that may Mimic Systemic Lupus Erythematosus

Q fever is a zoonosis caused by a Coxiella burnetii. Q fever is clinically variable, presenting as asymptomatic infection, pneumonia, hepatitis and endocarditis. Treatment of acute Q fever with doxycycline is usually successful. Autoantibodies, such as anti-mitochondrial antibodies, smooth muscle antibodies (SMA), anti-cardiolipin and lupus anticoagulant, often rise in acute Q fever infection. Some cases may occasionally meet the criteria for autoimmune disease like systemic lupus erythematosus. We report a first case of Q fever that may mimic systemic lupus erythematosus in Korea.

A Case of Q Fever that may Mimic Systemic Lupus Erythematosus

Q fever is a zoonosis caused by a Coxiella burnetii. Q fever is clinically variable, presenting as asymptomatic infection, pneumonia, hepatitis and endocarditis. Treatment of acute Q fever with doxycycline is usually successful. Autoantibodies, such as anti-mitochondrial antibodies, smooth muscle antibodies (SMA), anti-cardiolipin and lupus anticoagulant, often rise in acute Q fever infection. Some cases may occasionally meet the criteria for autoimmune disease like systemic lupus erythematosus. We report a first case of Q fever that may mimic systemic lupus erythematosus in Korea.

The Innate Immune Response in House Dust Mite-Induced Allergic Inflammation

Hypersensitivity to house dust mite (HDM; Dermatophagoides sp.) allergens is one of the most common allergic responses, affecting up to 85% of asthmatics. Sensitization to indoor allergens is the strongest independent risk factor associated with asthma. Additionally, >50% of children and adolescents with asthma are sensitized to HDM. Although allergen-specific CD4+ Th2 cells orchestrate the HDM allergic response through induction of IgE directed toward mite allergens, activation of innate immunity also plays a critical role in HDM-induced allergic inflammation. This review highlights the HDM components that lead to activation of the innate immune response. Activation may due to HDM proteases. Proteases may be recognized by protease-activation receptors (PARs), Toll-like receptors (TLRs), or C-type lectin receptors (CTRs), or act as a molecular mimic for PAMP activation signaling pathways. Understanding the role of mite allergen-induced innate immunity will facilitate the development of therapeutic strategies that exploit innate immunity receptors and associated signaling pathways for the treatment of allergic asthma.