The protein phosphatase-2A subunit PR130 is involved in the formation of cytotoxic protein aggregates in pancreatic ductal adenocarcinoma cells.

As a major source of cellular serine and threonine phosphatase activity, protein phosphatase-2A (PP2A) modulates signaling pathways in health and disease. PP2A complexes consist of catalytic, scaffolding, and B-type subunits. Seventeen PP2A B-type subunits direct PP2A complexes to selected substrates. It is ill-defined how PP2A B-type subunits determine the growth and drug responsiveness of tumor cells. Pancreatic ductal adenocarcinoma (PDAC) is a disease with poor prognosis. We analyzed the responses of murine and human mesenchymal and epithelial PDAC cells to the specific PP2A inhibitor phendione. We assessed protein levels by immunoblot and proteomics and cell fate by flow cytometry, confocal microscopy, and genetic manipulation. We show that murine mesenchymal PDAC cells express significantly higher levels of the PP2A B-type subunit PR130 than epithelial PDAC cells. This overexpression of PR130 is associated with a dependency of such metastasis-prone cells on the catalytic activity of PP2A. Phendione induces apoptosis and an accumulation of cytotoxic protein aggregates in murine mesenchymal and human PDAC cells. These processes occur independently of the frequently mutated tumor suppressor p53. Proteomic analyses reveal that phendione upregulates the chaperone HSP70 in mesenchymal PDAC cells. Inhibition of HSP70 promotes phendione-induced apoptosis and phendione promotes a proteasomal degradation of PR130. Genetic elimination of PR130 sensitizes murine and human PDAC cells to phendione-induced apoptosis and protein aggregate formation. These data suggest that the PP2A-PR130 complex dephosphorylates and thereby prevents the aggregation of proteins in tumor cells.

"Submarine-Shaped" Radial Forearm Flap for Simultaneous Reconstruction of Oral and Lower Lip Defects".

BACKGROUND: Reconstruction of the oral cavity commonly results in trismus and lip incompetence. AIM AND OBJECTIVES: In this study, we aim to describe an innovative design of a radial forearm free flap for resurfacing bilateral buccal defects and simultaneous functional lower lip reconstruction in a single stage. MATERIALS AND METHODS: Between January 2010 and December 2019, 6 males underwent simultaneous buccal and lower lip reconstruction with a radial forearm free flap. The mean age of the patients was 57.3 years (range, 50-68 years). The defects were caused by trismus release and due to previous treatments. The mean size of the defects was 17.9 cm in length and 3.25 cm in width. Flaps were harvested, including the proximal perforators of the radial vessels, and the inset began in the buccal area opposite the anastomosis side. RESULTS: Flap size ranged from 16 to 21 × 2 to 4 cm. The recipient vessels used were the superficial temporal (4) and facial (2). All flaps survived. Lip infection was seen in 2 cases and managed conservatively. The mean follow-up was 19.2 months (range, 12-28 months). The mean increase in the interincisal distance was 10.7 mm. Oral continence was good in all patients. Speech intelligibility was considered total in 4 patients and partial in the remaining 2. CONCLUSION: The radial forearm flap constitutes an option for simultaneous lower lip reconstruction and resurfacing of bilateral buccal areas after trismus release. The procedure provides a thin and pliable reconstruction using only 1 donor site and 1 set of recipient vessels.

Hypothalamic Pituitary Adrenal and Autonomic Nervous System Biomarkers of Stress and Tobacco Relapse: Review of the Research.

Tobacco smoking is a risk factor for countless diseases, and smoking relapse remains a major public health concern. Subjective reports of stress by smokers are a common theme for relapse, however, the role of objective stress-related biomarkers in predicting tobacco relapse risk has been less studied. The aim of this manuscript was to review existing literature on the connection between biomarkers of stress and smoking relapse. Overall, trends indicate that blunted hypothalamic-pituitary-adrenal (HPA) responses to acute stress, larger reductions in HPA biomarkers during the initial days of abstinence during cessation (compared to pre-cessation levels), and exaggerated autonomic responses to stress predict increased risk of relapse. In addition, successful cessation is followed by changes in stress biomarkers (e.g., reductions in cortisol and heart rate, HR). This review also identifies potential modifiers, such as methodological differences, biological sex, and chronic stress, to account for heterogeneity of findings within and across studies. In addition, we identify gaps in the literature and suggest future research directions focusing on the roles of genetics and gene expression as well as the influence of neurobiological mechanisms on stress and relapse risk. Future clinical implications of this research include identifying reliable indicators of relapse risk and the potential of pharmacotherapeutic treatments to target stress response systems to correct dysregulation and potentially reduce stress-related risk of relapse.

Awareness of Oral Submucous Fibrosis among the Quid-Chewing South-Asian Expatriates in the United Arab Emirates.

Oral submucous fibrosis (OSF) is a chronic disorder prevalent in South and Southeast Asia and is mainly related to the habit of chewing betel quid. Although there are numerous South-Asian studies about OSF, there is no study that evaluates the awareness of OSF among expatriate populations of South-Asian origin. Evaluated the awareness of OSF among South-Asian expatriate patients reporting to a dental hospital in Sharjah. Prevalidated questionnaires were given to 150 expatriate patients of South-Asian origin with quid-chewing habit reporting to the teaching clinics of a dental hospital in the United Arab Emirates. Among the 150 patients, 103 responded to the questionnaire. Among the 103 respondents, 11.65% were aware of OSF. Respondents living in shared residency and labor camps had significantly (P = 0.43) lower awareness of OSF compared to respondents living with their families. The results of our study show that the awareness of OSF is lower among the respondents living in labor camps and shared residencies. The younger respondents had more awareness of OSMF and were more likely to quit the quid-chewing habit.

Pharmacological degradation of ATR induces antiproliferative DNA replication stress in leukemic cells.

Mammalian cells replicate ~ 3 × 109 base pairs per cell cycle. One of the key molecules that slows down the cell cycle and prevents excessive DNA damage upon DNA replication stress is the checkpoint kinase ataxia-telangiectasia-and-RAD3-related (ATR). Proteolysis-targeting-chimeras (PROTACs) are an innovative pharmacological invention to molecularly dissect, biologically understand, and therapeutically assess catalytic and non-catalytic functions of enzymes. This work defines the first-in-class ATR PROTAC, Abd110/Ramotac-1. It is derived from the ATR inhibitor VE-821 and recruits the E3 ubiquitin-ligase component cereblon to ATR. Abd110 eliminates ATR rapidly in human leukemic cells. This mechanism provokes DNA replication catastrophe and augments anti-leukemic effects of the clinically used ribonucleotide reductase-2 inhibitor hydroxyurea. Moreover, Abd110 is more effective than VE-821 against human primary leukemic cells but spares normal primary immune cells. CRISPR-Cas9 screens show that ATR is a dependency factor in 116 myeloid and lymphoid leukemia cells. Treatment of wild-type but not of cereblon knockout cells with Abd110 stalls their proliferation which verifies that ATR elimination is the primary mechanism of Abd110. Altogether, our findings demonstrate specific anti-leukemic effects of an ATR PROTAC.

A Review of Recent Developments in Nanomaterial Agents for Water Shutoff in Hydrocarbon Wells.

Reducing water production from hydrocarbon wells is one of the major requirements to prolong the life span of production wells. Gel treatment is commonly regarded as one of the traditional cost-effective methods for water shut-off applications. Different gel systems have been developed to overcome the challenges of performing a successful water shut-off treatment. Each gel system has its advantages and disadvantages. A new proposed technology is to enhance the gel performance by utilizing nanomaterials in its composition. Nanomaterials such as nanosilica, nanoclay, and graphene can significantly modify gel properties to improve plugging efficiency. This paper provides a brief review of the added value of using nanomaterials in the structure of polymer in situ gel, preformed particle-gel, and nanosilica-based fluid. Nanomaterials such as nanoclay, nanosilica, and nanographene are capable of adjusting the properties of in situ gel, such as control of gelation time (9-10) hours and enhancing gel strength up to 4.5 times. Nanomaterials also improved the swelling ratio of the preformed particle-gel by up to 400%, accompanied by increased gel strength. Notably, nanosilica-based gels exhibit an exceptional plugging efficiency (100%). Additionally, the paper discusses how modeling can be used to overcome operational challenges in terms of placement and plugging performance.

Inhibitors of the tyrosine kinases FMS-like tyrosine kinase-3 and WEE1 induce apoptosis and DNA damage synergistically in acute myeloid leukemia cells.

Hyperactive FMS-like receptor tyrosine kinase-3 mutants with internal tandem duplications (FLT3-ITD) are frequent driver mutations of aggressive acute myeloid leukemia (AML). Inhibitors of FLT3 produce promising results in rationally designed cotreatment schemes. Since FLT3-ITD modulates DNA replication and DNA repair, valid anti-leukemia strategies could rely on a combined inhibition of FLT3-ITD and regulators of cell cycle progression and DNA integrity. These include the WEE1 kinase which controls cell cycle progression, nucleotide synthesis, and DNA replication origin firing. We investigated how pharmacological inhibition of FLT3 and WEE1 affected the survival and genomic integrity of AML cell lines and primary AML cells. We reveal that promising clinical grade and preclinical inhibitors of FLT3 and WEE1 synergistically trigger apoptosis in leukemic cells that express FLT3-ITD. An accumulation of single and double strand DNA damage precedes this process. Mass spectrometry-based proteomic analyses show that FLT3-ITD and WEE1 sustain the expression of the ribonucleotide reductase subunit RRM2, which provides dNTPs for DNA replication. Unlike their strong pro-apoptotic effects on leukemia cells with FLT3-ITD, inhibitors of FLT3 and WEE1 do not damage healthy human blood cells and murine hematopoietic stem cells. Thus, pharmacological inhibition of FLT3-ITD and WEE1 might become an improved, rationally designed therapeutic option.

Predictors of Developing a Complex Course of Osteomyelitis in Patients with Sickle Cell Anaemia.

Objectives: Despite the numerous advances in management strategies, treating osteomyelitis in individuals with sickle cell disease (SCD) remains a significant challenge, leading to severe long-term consequences. This study aimed to assess the key factors potentially linked to a complex progression of osteomyelitis in patients diagnosed with SCD. Methods: A cohort of 34 patients was identified and their progress was monitored over a span of 12 months during a 10-year period (2010-2020). The variables under investigation encompassed demographic and clinical traits, laboratory analyses and imaging data, as well as the treatment strategies employed. Results: The risk prediction model pinpointed 5 factors (severity of SCD, involvement of lower limbs, presence of bacteraemia, magnetic resonance image [MRI] findings and utilisation of surgical debridement) that exhibited an area under the curve (AUC) exceeding 0.7. Causative organisms were identified in 9 out of the total 34 patients (26.47%). A total of 17 patients displayed a severe course of SCD (AUC = 7.88), with MRI being highlighted as a valuable contributing factor (AUC = 7.88). Furthermore, 13 patients (38.2%) underwent surgical debridement, a procedure that yielded a statistically significant P value of 0.012 and an AUC of 0.714. Conclusion: Osteomyelitis within the context of severe SCD, particularly when accompanied by lower extremity infection, bacteraemia, positive MRI findings and the need for surgical debridement, emerges as a cluster of risk factors predisposing individuals to osteomyelitis relapse and a more complex disease course.

Review of Iraq’s nationwide attempts to transform medical school curricula over the last ten decades

Background: The first medical college in Iraq was established in 1927, adopting a subject-based curriculum. Aims:To provide a description of undergraduate medical education curricula in Iraq and how they developed since 1927. Methods: We identified Iraqi medical schools and curricula from local and global directories. Curricular data were compared to 3 educational benchmarks (Dale’s effectiveness of teaching methods, SPICES, Miller’s pyramid). We searched for studies describing curricula and modernization. Results: There are 34 medical colleges in Iraq (32 with identified curricula) with a wide scope of visions and aims adopting 3 types of curriculum: subject-based (SBC) 20 (63%), integrated (IC) 10 (31%) and problem-based learning (PBLC) 2 (6%). The majority of updates were SBC to IC, with only 1 moving from SBC to PBLC. The predominant type of curriculum at the start of instruction is SBC or IC. Although PBLC and IC provide opportunities for inquiry-driven competencies in the first 3 years only, none provide such opportunities in the clinical phase (last 3 years). Conclusions: Curricular reform needs to focus on modernizing the learning process/outcomes rather than reorganization of the teaching only. A new approach is needed to provide opportunities for competence and experience to prepare doctors to deal with challenges. One such approach would be the adoption of an outcomes-based curriculum model based on domains of competence with clearly defined outcomes/competencies achievable the time of graduation. All curricula should lead to the achievement of the same outcomes.

Isolated low grade prenatally detected unilateral hydronephrosis: do we need long term follow-up?

ABSTRACT Purpose: To assess the need for postnatal evaluation and the medium term outcome in patients with isolated unilateral low grade prenatally detected hydronephrosis. Materials and Methods: We prospectively selected 424 patients (690 kidney units) with a prenatal diagnosis of urinary tract dilatation between 2010 and 2013. We included only those patients with isolated unilateral low-grade hydronephrosis who underwent at least 2 postnatal ultrasound examinations. The Society for Fetal Urology (SFU) grading system was utilized for assessment of the hydronephrosis. We excluded patients with bilateral dilation or other urological abnormalities. The fate of hydronephrosis including resolution, stability or worsening was documented. Results: A total of 66 infants (44 boys and 22 girls) with antenatally diagnosed unilateral urinary tract dilation (23 right and 43 left) were identified. Ultrasounds showed SFU grade 1 hydronephrosis in 32 patients (48%) and SFU grade 2 hydronephrosis in 34 (52%). After a mean follow-up period of 32 months (range 12 to 60), 37 patients (56%) had complete resolution of hydronephrosis while the remaining 29 were stable (44%). None of our patients developed UTIs during follow-up and none required surgical intervention. Conclusions: Prenatally detected, isolated unilateral low-grade hydronephrosis usually have a favorable prognosis. All cases in our cohort showed either stability or resolution of hydronephrosis without any harmful consequences. Based on our findings on medium-term in this category of patients, long-term follow-up is not warranted.