Palmernilsson3142

Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance can occur when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or through the expression of constitutively active splice variants lacking the androgen binding domain entirely (e.g., ARV7). In this study, we are reporting the discovery of a novel AR-NTD covalent inhibitor 1-chloro-3-[(5-([(2S)-3-chloro-2-hydroxypropyl]amino)naphthalen-1-yl)amino]propan-2-ol (VPC-220010) targeting the AR-N-terminal Domain (AR-NTD). VPC-220010 inhibits AR-mediated transcription of full length and truncated variant ARV7, downregulates AR response genes, and selectively reduces the growth of both full-length AR- and truncated AR-dependent prostate cancer cell lines. We show that VPC-220010 disrupts interactions between AR and known coactivators and coregulatory proteins, such as CHD4, FOXA1, ZMIZ1, and several SWI/SNF complex proteins. Taken together, our data suggest that VPC-220010 is a promising small molecule that can be further optimized into effective AR-NTD inhibitor for the treatment of CRPC.Differentiated thyroid cancer (DTC) patients are usually known for their excellent prognoses. However, some patients with DTC develop refractory disease and require novel therapies with different therapeutic mechanisms. Targeting Wee1 with adavosertib has emerged as a novel strategy for cancer therapy. We determined the effects of adavosertib in four DTC cell lines. Adavosertib induces cell growth inhibition in a dose-dependent fashion. Cell cycle analyses revealed that cells were accumulated in the G2/M phase and apoptosis was induced by adavosertib in the four DTC tumor cell lines. The sensitivity of adavosertib correlated with baseline Wee1 expression. In vivo studies showed that adavosertib significantly inhibited the xenograft growth of papillary and follicular thyroid cancer tumor models. find more Adavosertib therapy, combined with dabrafenib and trametinib, had strong synergism in vitro, and revealed robust tumor growth suppression in vivo in a xenograft model of papillary thyroid cancer harboring mutant BRAFV600E, without appreciable toxicity. Furthermore, combination of adavosertib with lenvatinib was more effective than either agent alone in a xenograft model of follicular thyroid cancer. These results show that adavosertib has the potential in treating DTC.Colorectal cancer (CRC) develops from pre-cancerous cellular lesions in the gut epithelium, known as polyps. Polyps themselves arise through the accumulation of mutations that disrupt the function of key tumour suppressor genes, activate proto-oncogenes and allow proliferation in an environment where immune control has been compromised. Consequently, colonoscopic surveillance and polypectomy are central pillars of cancer control strategies. Recent advances in genomic sequencing technologies have enhanced our knowledge of key driver mutations in polyp lesions that likely contribute to CRC. In accordance with the prognostic significance of Immunoscores for CRC survival, there is also a likely role for early immunological changes in polyps, including an increase in regulatory T cells and a decrease in mature dendritic cell numbers. Gut microbiotas are under increasing research interest for their potential contribution to CRC evolution, and changes in the gut microbiome have been reported from analyses of adenomas. Given that early changes to molecular components of bowel polyps may have a direct impact on cancer development and/or act as indicators of early disease, we review the molecular landscape of colorectal polyps, with an emphasis on immunological and microbial alterations occurring in the gut and propose the potential clinical utility of these data.We defined prostate-specific antigen (PSA) thresholds from a well calibrated risk prediction model for identifying and excluding advanced prostate cancer (PCa). We retrieved 902 biopsied patients with a pre-biopsy PSA determination (Roche assay). A logistic regression model predictive for PCa including the main effects [i.e., PSA, age, histological evidence of glandular inflammation (GI)] was built after testing the accuracy by calibration plots and Hosmer-Lemeshow test for goodness of fit. PSA thresholds were derived by assuming a diagnostic sensitivity of 95% (rule-out) and 80% (rule-in) for overall and advanced/poorly differentiated PCa. In patients without GI, serum PSA concentrations ≤ 4.1 (6.1 μg/L (≥65) should address biopsy referral. In presence of GI, PSA did not provide a valid estimate for risk of advanced cancer because of its higher variability and the low pre-test probability of PCa. The proposed PSA thresholds may support biopsy decision except for patients with asymptomatic prostatitis who cannot be pre-biopsy identified.Myelodysplastic syndrome (MDS) describes a heterogeneous group of bone marrow diseases, now understood to reflect numerous germline and somatic drivers, characterized by recurrent cytogenetic abnormalities and gene mutations. Precursor conditions including clonal hematopoiesis of indeterminate potential and clonal cytopenia of undetermined significance confer risk for MDS as well as other hematopoietic malignancies and cardiovascular complications. The future is likely to bring an understanding of those individuals who are at the highest risk of progression to MDS and preventive strategies to prevent malignant transformation.Neck dissection is a surgical procedure reserved for thyroid cancer cases with clinically evident lymphatic invasion. Although neck dissection is a reliable and safe procedure, it can determine a significant morbidity involving a variety of structures of nervous, vascular and endocrine typology. A careful pre-operative study is therefore essential to better plan surgery. Surgical experience, combined with accurate surgical preparation and merged with adequate and specific techniques, can certainly help reduce the percentage of complications. In recent years, however, technology has also proved to be useful. Its crucial role was already recognized in the safeguard of the integrity of the laryngeal nerve through neuro-monitoring, but new technologies are emerging to help the preservation also of the parathyroid glands and other structures, such as the thoracic duct. These surgical skills combined with the latest technological advancements, that allow us to reduce the incidence of complications after neck dissection for thyroid cancer, will be reported in the present article. This topic is of significant interest for the endocrine and metabolic surgeons' community.

The analysis of cell-free DNA (cfDNA) for genetic abnormalities is a promising new approach for the diagnosis and prognosis of pancreatic cancer patients. Insights into the molecular characteristics of pancreatic cancer may provide valuable information, leading to its earlier detection and the development of targeted therapies.

We conducted a systematic review and a meta-analysis of studies that reported cfDNA in pancreatic ductal adenocarcinoma (PDAC). The studies were considered eligible if they included patients with PDAC, if they had blood tests for cfDNA/ctDNA, and if they analyzed the prognostic value of cfDNA/ctDNA for patients' survival. The studies published before 22 October 2020 were identified through the PubMED, EMBASE, Web of Science and Cochrane Library databases. The assessed outcomes were the overall (OS) and progression-free survival (PFS), expressed as the log hazard ratio (HR) and standard error (SE). The summary of the HR effect size was estimated by pooling the individual trial resulsistently

-positive patients (HR = 5.30, 95% CI 1.02-27.63).

The assessment of

mutation by liquid biopsy can be considered as an additional tool for the estimation of the disease course and outcome in PDAC patients.

The assessment of KRAS mutation by liquid biopsy can be considered as an additional tool for the estimation of the disease course and outcome in PDAC patients.

The aim of this study was to determine normative electrophysiological reference values of median sensory nerve conduction studies among security guards with the palmaris longus tendon (PLT).

Sensory nerve conduction studies of the median nerve using antidromic and orthodromic methods were conducted in the upper limbs of 101 healthy male security guards between the ages of 21 and 42 years. The presence of the PLT was recorded in both hands using a standard test. A scatter plot was used to determine the correlation between different parameters using the ortho and antidromic methods.

The mean age (years), weight (kg), height (cm), and BMI (kg/m2) were 28.77±5.14, 70.53±11.28, 171.71±7.12, and 23.91±3.45, respectively. In the median nerve (sensory) by antidromic method, the mean distal latency (DL) was 2.65±0.33ms and 2.64±0.37, SNCV (sensory nerve conduction velocity) was 53.45±5.28m/s and 53.84±5.68 and the amplitude was 27.33±12.38µV and 29.41±12.97 in the left- and right-hand wrist, respectively. By orthodromic method the DL was 2.54±0.53ms and 2.51±0.44, SNCV was 55.93±6.09m/s and 55.93±5.24 and the sensory nerve action potential amplitude was 12.00±8.82µV and 11.72±6.24 in the left and right hand, respectively. Spearman correlations were used to determine the variables influenced by hand sidedness.

The normative reference parameters of sensory nerve conduction velocity of the median nerve were established by both methods using a standardized technique.

The normative reference parameters of sensory nerve conduction velocity of the median nerve were established by both methods using a standardized technique.

To alleviate different pain intensities, morphine administration has been extensively used. However, prolonged administration of morphine leads to a progressive decline of its analgesic effect which limits their overall utility. Morphine tolerance is considered as a challenging issue for the treatment of both acute and chronic pain. We conducted this study in rats to investigate the effect of paroxetine on morphine tolerance when used preemptively or after morphine tolerance had developed.

Male Wistar rats (weight 250-300g, n=10) were used to evaluate the effects of paroxetine on tolerance to morphine. In order to induce tolerance, daily intraperitoneal injection of morphine (7mg/kg) was done. After tolerance induction, a group of animals received intraperitoneal injection of 10mg/kg paroxetine 30min prior to each morphine dose. In another trial, to investigate the potential of paroxetine to prevent tolerance to morphine, animals were pretreated with 10mg/kg paroxetine 30min before morphine administration. In the control groups, 10mL/kg of saline was injected. The behavioral test (tail-flick test) was done for all groups.

Our data showed that paroxetine significantly reversed tolerance to morphine when used after tolerance induction (p<0.001). However, administration of paroxetine before occurrence of tolerance had no effect.

We conclude that paroxetine could decrease tolerance to morphine when used after the occurrence of morphine tolerance, while it was not able to prevent morphine tolerance when administered preemptively.

IRIB.SBMU.MSP.REC.1394.098.

IRIB.SBMU.MSP.REC.1394.098.