Miracle-dz/UniFAR-FTUs huggingface dataset:
Biopharmaceutics classification system

Biopharmaceutics Classification System (BCS) has provided a mechanistic framework for understanding the concept of drug absorption in terms of permeability and solubility. This article reviews the criteria and issues for classifying drugs according to the BCS. Biowaiver extensions for drug or active pharmaceutical ingredient from different BCS classes with scientific basis are discussed as the current BCS guidelines by World Health Organization, Unites State Food and Drug Administration and European Medicines Agency allows for biowaivers based on conservative criteria. The article sheds light on the possible new criteria and class boundaries proposed for additional biowaivers based on the underlying physiology of the gastrointestinal tract in required cases. The potential applications of BCS in drug discovery, drug delivery and drug research as well as extension for BCS are discussed.
Impact of the severity of negative energy balance on gene expression in the subcutaneous adipose tissue of periparturient primiparous Holstein dairy cows: Identification of potential novel metabolic signals for the reproductive system

The severity of negative energy balance (NEB) in high-producing dairy cows has a high incidence among health diseases. The cow’s energy status during early lactation critically affects metabolic and reproductive parameters. The first objective of this study was to investigate by RNA-seq analysis and RT-qPCR the gene expression profile in white adipose tissue and by gene ontology and upstream regulation tools the relationships with energy metabolism and reproduction in two groups of primiparous dairy cows with extreme NEB statuses (NEB < -9 Mcal/day vs. NEB > -9 Mcal/day) around parturition. The second objective was to determine the potential involvement of a new adipokine identified as a candidate for the regulation of ovarian function in our RNA-seq analysis by using bovine primary granulosa culture, thymidine incorporation to determine cell proliferation and ELISA assays to measure progesterone secretion. The RNA-seq analysis revealed that 514 genes were over-expressed and 695 were under-expressed in the adipose tissue of cows with severe NEB (SNEB) and cows with moderate NEB (MNEB) during the -4 and 16 wkpp period. In addition, 491 genes were over-expressed and 705 genes were under-expressed in the adipose tissue of SNEB cows compared to MNEB cows. Among these differently expressed genes (DEGs), 298 were related to metabolic functions and 264 to reproductive traits. A set of 19 DEGs were validated by RT-qPCR, including CCL21 (C-C motif chemokine ligand 21). Moreover, CCL21, a gene known to be secreted by adipose tissue, was chosen for further analysis in plasma and ovaries. The use of next-generation sequencing technologies allowed us to characterise the transcriptome of white adipose tissue from primiparous cows with different levels of NEB during lactation. This study highlighted the alteration of the expression of genes related to lipid metabolism, including CCL21, which is released in the bloodstream and associated with the in vitro regulation of ovarian functions.
Effect of Stretching and Strengthening Shoulder Muscles on Forward Shoulder Posture in Competitive Swimmers

Context: Imbalanced shoulder muscles might cause poor posture in swimmers, which has been implicated as potential cause of injury. Objective: To determine whether a training program can reduce forward shoulder posture. Design: Prospective pseudorandomized. Setting: College swimming pool. Participants: 39 competitive swimmers (age 16 ± 2 years) divided into an exercise group (n = 24) and a control group (n = 15). Intervention: The experimental group performed a partner-stretching program on the anterior shoulder muscles and a strengthening regimen focusing on the posterior shoulder muscles for 6 weeks. The control group participated in normal swim-training activities. Main Outcome Measures: Shoulder posture was measured as the distance from the anterior acromion to a wall using a double-square method. Results: The experimental group significantly reduced the distance of the acromion from the wall in a resting posture (–9.6 ± 7.3 mm) as compared with the control group (–2.0 ± 6.9 mm). Conclusions: A trainin.
Acute ex vivo changes in brain white matter diffusion tensor metrics

Purpose Diffusion magnetic resonance imaging and tractography has an important role in the visualization of brain white matter and assessment of tissue microstructure. There is a lack of correspondence between diffusion metrics of live tissue, ex vivo tissue, and histological findings. The objective of this study is to elucidate this connection by determining the specific diffusion alterations between live and ex vivo brain tissue. This may have an important role in the incorporation of diffusion imaging in ex vivo studies as a complement to histological sectioning as well as investigations of novel neurosurgical techniques. Methods This study presents a method of high angular resolution diffusion imaging and tractography of intact and non-fixed ex vivo piglet brains. Most studies involving ex vivo brain specimens have been formalin-fixed or excised from their original biological environment, processes both of which are known to affect diffusion parameters. Thus, non-fixed ex vivo tissue is used. A region-of-interest based analysis of diffusion tensor metrics are compared to in vivo subjects in a selection of major white matter bundles in order to assess the translatability of ex vivo diffusion measurements. Results Tractography was successfully achieved in both in vivo and ex vivo groups. No significant differences were found in tract connectivity, average streamline length, or apparent fiber density. Significantly decreased diffusivity (mean, axial, and radial; p<0.0005) in the non-fixed ex vivo group and unaltered fractional anisotropy (p>0.059) between groups were observed. Conclusion This study validates the extrapolation of non-fixed fractional anisotropy measurements to live tissue and the potential use of ex vivo tissue for methodological development.
Tumorigenesis and Neoplastic Progression Decreased TIP30 Expression Promotes Tumor Metastasis in Lung Cancer

The HIV Tat-interacting protein (TIP30), also called CC3 or HTIP2, is encoded by Tip30 , a putative tumor-suppressor gene located on human chromosome 11p15.1. In this study, we investigated the role of TIP30 in the progression and metastasis of lung cancer. TIP30 expression was analyzed in 206 paired lung cancers and adjacent non-tumor tissues, as well as in 70 matched lymph node metastases using a high-den-sity tissue microarray. Results were compared with the clinicopathologic features of the patients from whom the tissues were taken. Low TIP30 expression levels were found in all 9 cases of small cell lung cancer and in 36.5% (72/197) of non-small cell lung cancer, which were correlated with lymph node metastasis in non-small cell lung cancer and with poor differentiation and advanced stage of tumor cells in squamous cell carcinoma. The immunostaining scores were significantly lower in the metastatic lesions than in the primary lesions. Down-regulation of TIP30 by a short hairpin RNA enhanced cell survival, migration, and invasion through Matrigel in vitro , and promoted lung metastasis and vascularization in nude mice. Further studies revealed that the down-regulation of TIP30 enhanced the expression of osteopontin, as well as matrix metalloproteinase-2 and vascular endothelial growth factor. Our results suggest that the down-regulation of TIP30
Intervertebral disc degeneration in dogs

Back pain is common in both dogs and humans, and is often associated with intervertebral disc (IVD) degeneration. The IVDs are essential structures of the spine and degeneration can ultimately result in diseases such as IVD herniation or spinal instability. In order to design new treatments halting or even preventing IVD degeneration, more basic knowledge of the disease process is needed. The aim of this thesis was to increase the knowledge of IVD degeneration in dogs and to evaluate the similarities and differences between IVD degeneration in dogs and humans, in order to establish whether spontaneous IVD degeneration occurring in both chondrodystrophic (CD) and non-chondrodystrophic (NCD) dog breeds can be used as translational animal models for human spine research. The key findings of the thesis were: • The division of the processes underlying canine IVD degeneration into chondroid or fibroid degeneration appears to be inaccurate. The biochemical, histopathological, and morphological alterations examined during the process of IVD degeneration were found to be similar in CD and NCD dog breeds. • IVD degenerative diseases were most common in CD breeds, especially in Dachshunds, and were 1.5 times more common in male than female dogs. Case fatality rates were found to be higher than previously suggested, with rates of 34% in the overall population, around 20% in most CD breeds, and over 50% in the NCD breeds at highest risk such as the Doberman and the German Shepherd Dog. • IVD degeneration in dogs could accurately be diagnosed, early in the degenerative process, by using low-field magnetic resonance imaging (MRI). The MRI based grading scheme used in humans could reliably be used in dogs, and was found to be highly correlated with pathological changes found post mortem. Early diagnosis facilitates the possibility of preemptive treatments. • A new nucleus pulposus prosthesis, made of an intrinsically radiopaque hydrogel, was tested ex-vivo in dogs. Surgical implantation of the prosthesis in canine lumbosacral IVDs via a dorsal laminectomy was clinically applicable. After absorbing fluid from the surrounding tissue the swollen implant could restore disc height, which could be monitored by radiography, computed tomography and MRI. • Many similarities were found between the processes of IVD degeneration in humans and CD and NCD dog breeds. Both dog-types may serve as translational animal models of spontaneous IVD degeneration for human research. Synergistic effects of studying IVD degeneration in veterinary patients could lead to new treatment modalities for both dogs and humans, a reduced need for animal testing, and lower cost of research. It is also likely that spontaneous IVD degeneration in dogs more resembles the true disease process, as it occurs in humans, than induced IVD degeneration in experimental animals.
Increased tissue factor expression is associated with reduced survival in non-small cell lung cancer and with mutations of TP53 and PTEN.

BACKGROUND Tissue factor (TF), the main initiator of blood coagulation, is also a signaling protein that regulates cancer progression. TF synthesis was recently shown to be affected by tumor suppressor genes (TSGs) in tumor cell lines. We therefore studied TF gene (F3) expression and the status of genes coding for tumor protein p53 (TP53), phosphatase and tensin homolog (PTEN), and serine/threonine kinase 11 (STK11) in non-small cell lung cancer (NSCLC). Heparanase (HPSE) gene expression was also measured because this endo-beta-D-glucuronidase was recently shown to enhance TF gene expression. METHODS TF and heparanase mRNA expression was measured by real-time PCR in 53 NSCLC tumors. Exons 5-8 of TP53 were sequenced from genomic DNA. Mutations of PTEN and STK11 were screened by multiplex ligation-dependent probe amplification. RESULTS TF mRNA levels were significantly higher in T(3)-T(4) tumors (P = 0.04) and in stages III-IV of NSCLC (P = 0.03). Mutations of TP53, STK11, and PTEN were identified in 20 (37.7%), 21 (39%), and 20 (37.7%) of tumors, respectively. TF expression was higher in mutated TP53 (TP53(Mut)) (P = 0.02) and PTEN(Mut) (P = 0.03) samples. Moreover, TF mRNA increased from 2700 copies (no mutation) to 11 6415 when 3 TSG were mutated. Heparanase gene expression did not differ according to TF gene (F3) expression or TSG mutation. The median survival time was shorter in patients with tumor TF mRNA levels above median values (relative risk 2.2; P = 0.03, multivariate analysis) and when TP53 was mutated (relative risk 1.8; P = 0.02). CONCLUSIONS These results provide clear evidence that combined oncogene events affecting TSG dramatically increase TF gene expression in lung tumors. Moreover, this study suggests that TF gene expression could be used as a prognostic marker in NSCLC.
Determining the factors affecting recurrence in bipolar I disorder using Andersen-Gill counting process model

Background and purpose: Bipolar disorder is a severe psychiatric disorder with a variety of natural courses and manifestations, and a recurrent nature. The aim of this study was to determine the effective factors on recurrence using Andersen-Gill counting process model. Materials and methods: In an ambidirectional cohort study (4 years retrospective and 1 year prospective from 2007 to 2012), 255 patients (141 men, and 114 women) with bipolar type I disorder and history of hospitalization in Zare psychiatric center (Sari, Iran) were studied. Demographic, psychiatric and other variables related to recurrence were gathered from patients' medical records. Andersen-Gill counting process model via Statistical Package of STATA was used to determine predictive variables of recurrence. Results: 693 recurrences occurred during the 5 years follow-up period; all the patients experienced recurrence at least once, 29 patients (11.4%) only once, 90 (35.3%) twice, 87 (34.1%) thrice, 25 (9.8%) four times, 21 (8.2%) five times, and 3 (1.2%) six time. Counting process regression model showed that the number of previous episodes and psychiatric family history in first-degree relatives (hazard ratio > 1; P < 0.05) increased the probability of recurrence; and presence of psychotic features in each recurrence decreased hazard of recurrence (hazard ratio < 1; P < 0.05). Conclusion: Bipolar disorder has a high rate of recurrence. Predictor variables include number of previous episodes, first-degree relatives' psychiatric family history and presence of psychotic features in each recurrence.
GPs' Confidence in and Barriers to Implementing Smoking Cessation Activities: Compared to Dentists, Dental Hygienists and Pharmacists

GP smoking cessation interventions have been found to be highly efficacious. However, reported uptake is low, and little is known about barriers or comparisons with other health professionals. The objectives of this study were to examine GPs' provision of smoking cessation activities, confidence and perceived barriers, and compare the results to other health professions (dentists, dental hygienists and pharmacists). A random sample of South Australian GPs (n = 269) were surveyed. Comparisons were made with dentists, dental hygienists and pharmacists for whom similar data had been obtained. Participants were surveyed on their confidence, perceived barriers, level of smoking cessation activity and practice and demographic factors. GPs reported greater provision of and greater confidence in a range of brief smoking cessation interventions than other professions and perceived fewer barriers to the provision of smoking cessation activities. Confidence and system barriers were reported as the most common factors that impeded greater provision of smoking cessation activities. It was concluded that confidence and system barriers need to be addressed to increase rates of smoking cessation interventions provided by these professional groups. Skills-based training that develops confidence would be beneficial for all health professional groups and would increase the number of smokers receiving advice and assistance to quit smoking.
Solexa sequencing: decoding genomes on a population scale.

It is has now been some 17 years since David Klenerman and I (Fig. 1) conceived a project that would subsequently enable rapid whole human genome sequencing. The core thinking that led to Solexa Sequencing was sparked by observations made during basic exploratory research carried out in our laboratories during the mid to late 1990s, and the redirection of these observations toward DNA sequencing was an unintended consequence. The founding ideas and proof-of-concept experiments were carried out at the University of Cambridge. The first commercial sequencing system was subsequently developed at Solexa Limited, a company we founded in 1998. Illumina Inc. acquired Solexa in early 2007 and made further improvements that led to several new sequencing systems. Today, the technology is being used to routinely decode human genomes for medical research, clinical decision-making, and basic science, all at a cost and speed that make population-scale sequencing practical. The journey from concept to reduction to practice has already gone beyond my expectations in terms of performance, adoption, and early insights, yet the era of clinical whole genome sequencing is perhaps only just beginning. Fig. 1. David Klenerman and me at our “local,” where we have enjoyed much creative discussion (and beer). In the mid-1990s, in the University Chemical Laboratories, Cambridge, David Klenerman and I were using fluorescence single-molecule spectroscopy to observe the synthesis of DNA by a polymerase enzyme using fluorescently encoded nucleotides. The work itself and the grant proposal that supported it were fundamental in nature and said nothing of sequencing. The struggle and attempts to improve the experimental design to optimize what we wished to observe suggested to us a means to decode a strand of immobilized DNA by single-molecule fluorescence imaging. It was not immediately clear what the benefits of decoding DNA on a surface would be, until our awareness of DNA microarrays prompted the realization that the decoding of immobilized DNA could be made parallel …
A case study from the Sunnybrook and Women's College Health Sciences Centre: Do clinical trials of neoadjuvant chemotherapy for locally advanced breast cancer (LABC) overestimate the actual response rates observed in clinical practice?

A 48-year-old premenopausal woman was referred to our locally advanced breast cancer (LABC) programme by her surgeon. She presented with a 4month history of a slowly growing mass in the left breast. Assessment by the surgeon was suspicious for malignancy and a core biopsy confirmed the presence of an oesterogen receptor (ER) and progesterone receptor (PR) negative, HER2/neu negative breast cancer. Staging chest X-ray, liver ultrasound, and bone scan were all normal. On clinical examination the left breast was replaced with tumour. It was fixed to skin with peau d’orange but was not fixed to the chest wall. The tumour within the breast measured 10 8 cm. The patient also had mobile but matted axillary lymph nodes measuring 5 1 cm. She therefore had clinical T4b, N2a (stage IIIB) disease. She was treated on a standard protocol of 3 weekly AC for 4 cycles followed by 3 weekly taxotere for 4 cycles. This was to be followed by surgery and full field radiotherapy to both the chest wall and local lymph node sites. After completion of chemotherapy, examination of her breasts revealed a 5 cm diameter soft thickening in her left breast and no palpable axillary lymphadenopathy. Pathology assessment after mastectomy showed a residual 3 cm tumour, Bloom and Richardson grade 2/3, in the breast. Single tumour cells and an occasional group of tumour cells were present within the epidermis and no lymph nodes were involved. All resection margins were clear. The patient wanted to know what additional systemic therapy was needed in view of her residual disease at the time of mastectomy.
Clinical Trials in Precision Oncology.

BACKGROUND Availability of genomic information used in the management of cancer treatment has outpaced both regulatory and reimbursement efforts. Many types of clinical trials are underway to validate the utility of emerging genome-based biomarkers for diagnostic, prognostic, and predictive applications. Clinical trials are a key source of evidence required for US Food and Drug Administration approval of therapies and companion diagnostics and for establishing the acceptance criteria for reimbursement. CONTENT Determining the eligibility of patients for molecular-based clinical trials and the interpretation of data emerging from clinical trials is significantly hampered by 2 primary factors: the lack of specific reporting standards for biomarkers in clinical trials and the lack of adherence to official gene and variant naming standards. Clinical trial registries need specifics on the mutation required for enrollment as opposed to allowing a generic mutation entry such as, "EGFR mutation. " The use of clinical trials data in bioinformatics analysis and reporting is also gated by the lack of robust, state of the art programmatic access support. An initiative is needed to develop community standards for clinical trial descriptions and outcome reporting that are modeled after similar efforts in the genomics research community. SUMMARY Systematic implementation of reporting standards is needed to insure consistency and specificity of biomarker data, which will in turn enable better comparison and assessment of clinical trial outcomes across multiple studies. Reporting standards will facilitate improved identification of relevant clinical trials, aggregation and comparison of information across independent trials, and programmatic access to clinical trials databases.
Extreme Weight Gain due to Short-term Use of Low-dose Propranolol

Several cases have been reported to gain weight due to long - term treatment with propranolol. According to FDA, no case has been previously reported of sharp increase in gaining weight due to short - term treatment with low - dose propranolol. A 34 - year - old wom an with a diagnosis of generalized anxiety disorder and obsessive - compulsive disorder was treated with sertraline (100 mg) which was taken twice daily (morning and evening). She was also given trazodone (50 mg) and haloperidol (0.5 mg) once daily. Four mon ths after starting the treatment, she was also treated with propranolol (20 mg) twice daily due to akathisia and tremor. After a short period (two weeks), she was not willing to continue taking propranolol anymore and stopped using it because of uncontroll able overeating and weight gain (3kg). Restarting the drug again led to increased appetite. Despite the drug's effect on reducing total energy consumption and body's thermogenic response to food, it is believed that individual and unique properties may als o affect the metabolism.
Challenges in the management of cancer pain in elderly population: A review

Elderly people are more susceptible to the experience of pain than any other sector of the population. Neoplasia is an important cause of pain in the elderly population. The prevalence of persistent pain in older persons living in a care home setting is estimated at 45-80%, thus highlighting that persistent pain in older people is widespread and problematic in these settings. This article reviews the difficulties in the management of pain in the elderly population and the important differences from other population besides describing the various pain assessment tools, pharmacologic and nondrug management of pain.
Effects of septoplasty on nasal and oropharyngeal microbial flora

We characterized the changes in oropharyngeal and nasal flora of the patients with a deviated nasal septum before and after septoplasty. Patients who underwent septoplasty for nasal septal deviation were included in this study. Nasal and oropharyngeal cultures were taken with a sterile cotton swab preoperatively and one month after septoplasty. Antimicrobial susceptibility testing was performed using the disc method. Fifty-nine patients with a deviated nasal septum were included in the study: 29 women and 30 men, whose ages ranged from 18 to 40 years. There was no significant difference between the preoperative and postoperative (one month after surgery) isolated bacteria of the nasal and oropharyngeal regions. Septoplasty did not change the nasal and oropharyngel microbial flora in patients who underwent septoplasty for nasal septal deviation. Key words: Septoplasty, nasal microbial flora and oropharyngeal microbial flora.