Identification of an Allosteric Small-Molecule Inhibitor Selective for the Inducible Form of Heat Shock Protein 70

Inducible Hsp70 (Hsp70i) is overexpressed in a wide spectrum of human tumors and its expression correlates with metastasis, poor outcomes, and resistance to chemotherapy in patients. Identification of small molecule inhibitors selective for Hsp70i could provide new therapeutic tools for cancer treatment. In this work, we used fluorescence-linked enzyme chemoproteomic strategy (FLECS) to identify HS-72, an allosteric inhibitor selective for Hsp70i. HS-72 displays the hallmarks of Hsp70 inhibition in cells, promoting substrate protein degradation and growth inhibition. Importantly, HS-72 is selective for Hsp70i over the closely related constitutively active Hsc70. Studies with purified protein show HS-72 acts as an allosteric inhibitor, reducing ATP affinity. In vivo HS-72 is well-tolerated, showing bioavailability and efficacy, inhibiting tumor growth and promoting survival in a HER2+ model of breast cancer. The HS-72 scaffold is amenable to resynthesis and iteration, suggesting an ideal starting point for a new generation of anticancer therapeutics targeting Hsp70i

Nuclear pore complex dynamics in interphase and mitosis

Bibliography: p. 201-23

Frequency of the Hemochromatosis Gene (HFE) Variants in a Jordanian Arab Population and in Diabetics from the Same Region

Hereditary HFE-linked hemochromatosis is a frequent recessive disorder among individuals of northern European ancestry. The clinical characteristic of this disease is the gradual accumulation of iron in internal organs, which ultimately may lead to organ damage and death. Three allelic variants of HFE gene have been correlated with hereditary hemochromatosis: C282Y is significantly associated with hereditary hemochromatosis in populations of Celtic origin, H63D and S65C are associated with milder form of iron overload. In this study we performed mutation analysis to identify allele frequency of the three variants of HFE gene in Jordanian Arab population, to assess deviations of these frequencies from those detected elsewhere, and to determine if there is an increased frequency of these variants in a diabetic population (Type 2 diabetes) from the same area. DNA was extracted from blood samples of 440 individuals attending King Abdullah University Hospital for ambulatory services. We used polymerase chain reaction (PCR) to amplify exons 2 and 4 of the HFE gene then restriction fragment length polymorphism (RFLP) method to detect the variants. There were neither homozygous nor heterozygous for C282Y variant. For the H63D variant, 0.68% were homozygous and 21.1% were heterozygous. For the S65C variant, there were no homozygous and 0.23% were heterozygous. Allelic frequencies were, 0%, 11.25%, and 0.11% for C282Y, H63D, and S65C, respectively. Our samples were subdivided into two categories of type 2 diabetic (89 cases) and controls (blood donors, 204 cases) and compared with regard to the H63D variant. Both groups did not have homozygous H63D variant. H63D heterozygous in diabetics were 23.60% and in blood donor controls 22.55%. Allelic frequency of the mutant H63D allele was 11.80% in diabetics and 11.27% for the blood donor controls. This is the first study to show the frequency of the three hemochromatosis gene variants in Jordan with the interesting finding of no C282Y allele detected in 440 samples. Additionally, no significant difference was observed in H63D variant frequency in type 2 diabetics as compared to controls

Identification of a novel WFS1 homozygous nonsense mutation in Jordanian children with Wolfram syndrome

Syftet med studien var att undersöka om Herzbergs tvåfaktorteori har relevans i praktiken idag inom läraryrket. Studien är kvalitativ med deduktiv ansats utifrån Herzbergs tvåfaktorteori. Totalt 10 semistrukturerade intervjuer utfördes med lärare från högstadie- och universitetsnivå vilka sedan analyserades tematiskt. Resultatet visade att Herzbergs teori fortfarande är tillämpningsbar inom yrket lärare. Resultatet visade däremot på att det fanns skillnader i vad för faktorer som är av mest vikt hos lärarna gentemot vad Herzberg påstod. De mest avgörande faktorerna för arbetsmotivation hos lärarna var eget ansvar, bekräftelse och den psykosociala arbetsmiljön. Förslag till vidare forskning är att säkerhetsställa rangordningen av faktorerna som har störst betydelse för arbetsmotivationen inom läraryrket. Ett annat förslag till vidare forskning är att se om det finns faktorer från Herzbergs tvåfaktorteori som rangordnas annorlunda inom andra yrkeskategorier. The purpose of the study is to examine whether Herzberg's two-factor theory is still relevant in practice today in the teaching profession. The study is qualitative with a deductive approach based on Herzberg's two-factor theory. A total of 10 semi-structured interviews were conducted with high school and university teachers, which were then analyzed thematically. The result showed that Herzberg's theory is still applicable and valid in the profession of teaching. The results, on the other hand, show that there are differences in which factors that are the most important for the teachers in relation to what Herzberg claimed. The most important factors for the teachers' work motivation are having their own responsibility over their time, recognition and the psychosocial work environment. Suggestions for further research are to secure the ranking of the factors that are most important for the work motivation within the teaching profession. Also evaluate if there are factors from Herzberg's two-factor theory that are ranked differently in other professions.

LPS protects macrophages from AIF-independent parthanatos by downregulation of PARP1 expression, induction of SOD2 expression, and a metabolic shift to aerobic glycolysis

L

Basal Cell Carcinoma Pathology Requests and Reports Are Lacking Important Information

Introduction. Basal cell carcinoma (BCC) is the most common cancer affecting humans. Luckily it has negligible risk for metastasis; however it can be locally destructive to surrounding tissue. The diagnosis of this tumor relies on clinical and dermoscopic features; however confirmation requires biopsy and histologic examination. Based on clinical and pathologic findings, BCC is classified as low or high risk subtype. The clinician requesting pathology examination for BCC should provide the pathologist with detailed information including patient details, relevant clinical and medical history, site and type of the biopsy, and whether this is a primary or recurrent lesion. The pathologist on the other hand should write an adequate report containing a minimum of core set of parameters including type of BCC, depth of invasion, presence of lymphovascular or perineural invasion, and the excision margins. Objectives. The objective of this study is to evaluate whether requests by clinicians and pathology reports of BCC are adequate. Methods. This is a retrospective analysis done at the dermatology department, faculty of medicine at Jordan University of Science and Technology, Irbid, Jordan. Reports for the period from January 2003 to December 2017 were retrieved and analyzed for data completeness. Results. Most clinical request forms of BCC provided by clinicians are inadequate and lack important relevant information especially in regard to lesion history, patient medical history, and whether BCC is a primary or a recurrent one. Pathology reports for BCC cases also have significant deficiency especially in describing the histologic subtype, depth of invasion, and presence of lymphovascular and perineural invasion. However, the tumor excision margins are adequately described in almost all reports. Conclusions. The study shows that clinicians do not provide adequate clinical information when submitting a request for histopathologic examination of BCC. Similarly, pathologists write incomplete reports that lack important pathologic features. Having pre-set forms (electronic proforma) can help overcome missing information