Serum TK1 protein and C-reactive protein correlate to treatment response and predict survival in dogs with hematologic malignancies

Thymidine kinase 1 (TK1), involved in DNA precursor synthesis, is used as a serum biomarker in cancer diagnostics in both human and veterinary medicine. We investigated the utility of serum TK1 protein (TK1p) and TK1 activity (TK1a) determinations for prognosis and monitoring of canine hematological malignancies. The combination of TK1p or TK1a with canine C-reactive protein (CRP) determinations was also investigated. Serum samples from 51 client-owned dogs with naive hematological malignancies and from 149 healthy subjects were included. Serum TK1p levels were determined using a prototype TK1-ELISA, TK1a using the [H-3]- dThd phosphorylation assay, and CRP using an immunoturbidimetric assay. Mean TK1p in sera from dogs with tumors was significantly higher than from healthy dogs (mean +/- SD = 3.9 +/- 5.9 vs. 0.45 +/- 0.15 ng/mL). Similarly, TK1a in hematological malignancies was significantly higher than in healthy dogs (mean + SD = 15.1 +/- 31.3 vs. 0.96 +/- 0.33 pmol/min/mL). The receiver-operating characteristic indicated that a combination of TK1p or TK1a with CRP gave higher sensitivity than either biomarker alone for the prognosis of hematological malignancies. Median pretreatment TK1p and TK1a levels were significantly higher than in dogs in remission and correlated with clinical outcome. Kaplan-Meier curve analysis showed that naive dogs with high TK1p, TK1a, and CRP had significantly shorter survival. This study present two new polyclonal antibodies used in an ELISA system to determine TK1p. The study also show that combining TK1p or TK1a with CRP gave higher sensitivity than either biomarker alone. Monitoring patients in the study while undergoing chemotherapy, suggests that the TK1 + CRP combination could be useful in a biomarker panel, possibly aiding the prognosis and therapy monitoring of hematological malignancies in dogs.Peer reviewe

Serum TK1 protein and C-reactive protein correlate to treatment response and predict survival in dogs with hematologic malignancies

Thymidine kinase 1 (TK1), involved in DNA precursor synthesis, is used as a serum biomarker in cancer diagnostics in both human and veterinary medicine. We investigated the utility of serum TK1 protein (TK1p) and TK1 activity (TK1a) determinations for prognosis and monitoring of canine hematological malignancies. The combination of TK1p or TK1a with canine C-reactive protein (CRP) determinations was also investigated. Serum samples from 51 client-owned dogs with naive hematological malignancies and from 149 healthy subjects were included. Serum TK1p levels were determined using a prototype TK1-ELISA, TK1a using the [H-3]- dThd phosphorylation assay, and CRP using an immunoturbidimetric assay. Mean TK1p in sera from dogs with tumors was significantly higher than from healthy dogs (mean +/- SD = 3.9 +/- 5.9 vs. 0.45 +/- 0.15 ng/mL). Similarly, TK1a in hematological malignancies was significantly higher than in healthy dogs (mean + SD = 15.1 +/- 31.3 vs. 0.96 +/- 0.33 pmol/min/mL). The receiver-operating characteristic indicated that a combination of TK1p or TK1a with CRP gave higher sensitivity than either biomarker alone for the prognosis of hematological malignancies. Median pretreatment TK1p and TK1a levels were significantly higher than in dogs in remission and correlated with clinical outcome. Kaplan-Meier curve analysis showed that naive dogs with high TK1p, TK1a, and CRP had significantly shorter survival. This study present two new polyclonal antibodies used in an ELISA system to determine TK1p. The study also show that combining TK1p or TK1a with CRP gave higher sensitivity than either biomarker alone. Monitoring patients in the study while undergoing chemotherapy, suggests that the TK1 + CRP combination could be useful in a biomarker panel, possibly aiding the prognosis and therapy monitoring of hematological malignancies in dogs.Peer reviewe

A Dual Biomarker TK1 Protein and CA125 or HE4-Based Algorithm as a Better Diagnostic Tool than ROMA Index in Early Detection of Ovarian Cancer

Simple Summary Ovarian cancer is one of the most difficult tumors to detect and manage. Usually, it is diagnosed in late stage of the disease which is associated with poor prognosis. Therefore, it is important to detect this cancer in the early stages to improve overall survival. In this study, we determined TK1 protein and TK1 activity levels as well as the biomarkers CA 125, HE4, and the ROMA index. Elevated TK1 protein levels were found in both benign and ovarian tumor (borderline and malignant ovarian cancer) patients. The combination of TK1 protein with CA 125 or HE4 showed higher sensitivity compared to the ROMA index. Therefore, the TK1 protein is a promising serum biomarker that can complement CA 125 or HE4 in the diagnostics of the early stages of ovarian cancer. Background: The early detection of ovarian cancer is presently not effective, and it is crucial to establish biomarkers for the early diagnosis of ovarian cancer to improve the survival of patients. Materials and methods: The aim of this study was to investigate the role of thymidine kinase 1 (TK1) in combination with CA 125 or HE4 to serve as a potential diagnostic biomarkers for ovarian cancer. In this study, a set of 198 serum samples consisting of 134 ovarian tumor patients and 64 healthy age-matched controls were analyzed. The TK1 protein levels in serum samples were determined using the AroCell TK 210 ELISA. Results: A combination of TK1 protein with CA 125 or HE4 showed better performance than either of them alone in the differentiation of early stage ovarian cancer from the healthy control group, but also a significantly better performance than the ROMA index. However, this was not observed using a TK1 activity test in combination with the other markers. Furthermore, the combination of TK1 protein and CA 125 or HE4 could differentiate early stage disease (stage I, II) more efficiently from advanced-stage (stage III, IV) disease (p < 0.0001). Conclusions: The combination of TK1 protein with CA 125 or HE4 increased the potential of detecting ovarian cancer at early stages

A comparative study of the treatment outcomes in Alcoholic Liver Disease patients treated with Ursodeoxycholic acid and Methionine along with Abstinence (Placebo)

Liver is extremely active organ in the body. Ethanol toxicity on liver is a function of duration of alcoholism, amount of daily intake and patient's nutrition. Ethanol is oxidized in the liver to acetaldehyde , a compound considerably more toxic than ethanol itself. ATP synthesis rate is reduced in the liver cells when exposed to ethanol... ethanol is metabolised by two ways.Chronic ethanol consumption&nbsp; has a profound stimulatory effect on microsomal enzymes, in particular cytochrome CYP2E1.&nbsp;Alcohol increases the flow of blood in the portal and hepatic vascular resistance results increased portal pressure and collateral blood flow which causes the visceral bleeding in patients with alcoholic cirrhosis and portal hypertension. The aim of the study is to evaluate the outcome of ursodeoxycholic acid (300mg),methionine (400mg)and abstinence in the treatment of alcoholic liver disease and the objective is to achieve the following end points(primary end point -change from baseline in particular LFT parameter-albumin and CBP parameters such as PT and INR ratio)(secondary end point- effects of ursodeoxycholic acid and methionine on other LFT parameters such as total bilirubin, SGOT, SGPT along with changes in the&nbsp; above parameters in patients with abstinence.). In particular Liver function test parameters meant for the study are Bilirubin, SGOT, SGPT, Albumin. By assessing the particular parameters of the study, we concluded the following outcomes: At the end of the study, group 1 has shown 60% improvement, Group 2 has shown 50 % improvement from baseline to the end of the study. Group 3 has not shown much improvement when compared to the study medications i.e there is an overall improvement of only 30 % from baseline. By the end of the study scruitinizing all the laboratory parameters it is&nbsp;&nbsp; observed that of the three groups, group 1 and group 2 has better treatment outcomes than group 3 and hence it is concluded that medical intervention is more effective over complete abstinence and concluded that early medical intervention is a better option for better outcomes

A simple randomized comparative study to evaluate the efficacy of 0.7% w/v Olopatadine hydrochloride ophthalmic solution and the Fixed Dose Combination of 0.1% w/v Olopatadine hydrochloride and 0.4% w/v Ketorolac tromethamine ophthalmic solution for the

Conjunctivitis is defined as the inflammation of the conjunctiva. Allergic conjunctivitis is an acute, intermittent or chronic inflammation of the conjunctiva due to air borne allergens. Allergic reactions occur when the immune system is hypersensitive to normally harmless environmental substances, called allergens. Allergic conjunctivitis is an increasingly prevalent allergic reaction and currently 40% of global population is suffering from allergic conjunctivitis. Being an immunopathological disease, Conjunctival mast cell degranulation plays a major role in ocular allergic disease and so treatment options should be concentrated on preventing degranulation or of antagonizing the effects of the primary mediator, histamine. Commonly used medications are: Topical OTC antihistamines (eg, ketotifen) , topical prescription antihistamines (eg, olopatadine, bepotastine, alcaftadine), NSAIDs (eg, ketorolac), or mast cell stabilizers (eg, nedocromil, cromolyn, azelastine) and can be used separately or in combination. In our study, the safety profile of Olopatadine 0.7% is comparable with fixed dose combination of Olopatadine 0.1% and ketorolac tromethamine 0.4% by assessing the reduction in the severity of four parameters (ocular itching, conjunctival hyperemia, chemosis and tearing) of allergic conjunctivitis over 14 days of daily treatment. Ours is a Prospective case observational study conducted from August 2018-January 2019. A total of 80 patients were screened from the ophthalmology outpatient department. All the subjects who fulfilled eligibility criteria were randomly assigned in equal proportions into two arms i.e, group-1(patients receiving 0.7% olopatidine Hcl eye drops) &amp; group-2( patients receiving 0.1% olopatidine Hcl+ 0.4% ketorolac tromethamine eye drops.). It was observed that there was a significant difference in the percentage reduction of all the four parameters in the group 1 (i.e; patients treated with monotherapy) than the group 2 (i.e; patients treated with combination therapy). From this we concluded that monotherapy of 0.7% Olopatadine hydrochloride ophthalmic solution was found to be more effective in&nbsp; reducing the clinical signs and symptoms of allergic conjunctivitis than dual combination therapy of 0.1% Olopatadine&nbsp; hydrochloride + 0.4% Ketorolac tromethamine ophthalmic solution. &nbsp

Drug Utilization Evaluation of Piperacillin and Tazobactum at a Tertiary Care Center in Hyderabad, India.

Drug use evaluation is an ongoing, systematic, criteria-based program of medicine evaluations that will help ensure appropriate medicine use. If therapy is determined to be inappropriate, interventions with providers or patients will be necessary to optimize pharmaceutical therapy. Empirical therapy forms the basis of treatment in India mostly and it is the responsibility of DTC (Drugs and therapeutics committee) to organize a DUE study and adopt suitable protocol for controlling irrational drug use. In our study we have developed a data collection form based upon WHO guidelines for conducting a DUE study on piperacillin and tazobactum use evaluation. To assess the usage of piperacillin and tazobactum at a tertiary care center Hyderabad compared to the indications for piperacillin and tazobactum use and standard treatment guidelines and provide recommendations to improve rational use of piperacillin and tazobactum at these hospitals and reduce the development of further antibiotic resistance, prevent ADRs associated with the drug, and to reduce the economic burden on the patient with inappropriate use. For conducting the evaluation process we had followed the standard guide lines formulated by WHO. The gender distributions of casesheets were male- 42, female- 23. Indication wise the distribution of case sheets were mostly treated for surgical prophylaxis, prophylaxis and infections. Out of 65 cases 65 (99%) has met the established criteria, they are as per STGs. Illness most frequently treated with piperacillin and tazobactum is ckd with acute deterioration (29.23%). The minimum number of days of treatment was 3 day and the maximum number of days of treatment was 14days.&nbsp; All patient folders evaluated with regards to HD, SEPTIC SHOCK, PNEMOMEDIATINM etc were found to meet the standard criteria appropriate for piperacillin and tazobactum use with respect to dose, and dose frequency. However, in the case of dose duration the evaluation was found to be largely inappropriate for all the justified indications.&nbsp; &nbsp

Lhx8 regulates primordial follicle activation and postnatal folliculogenesis

Background: The early stages of ovarian follicle formation-beginning with the breakdown of germ cell cysts and continuing with the formation of primordial follicles and transition to primary and secondary follicles-are critical in determining reproductive life span and fertility. Previously, we discovered that global knockouts of germ cell-specific transcriptional co-regulators Sohlh1, Sohlh2, Lhx8, and Nobox, cause rapid oocyte loss and ovarian failure. Also factors such as Nobox and Sohlh1 are associated with human premature ovarian failure. In this study, we developed a conditional knockout of Lhx8 to study oocyte-specific pathways in postnatal folliculogenesis. Results: The conditional deficiency of Lhx8 in the oocytes of primordial follicles leads to massive primordial oocyte activation, in part, by indirectly interacting with the PI3K-AKT pathway, as shown by synergistic effects on FOXO3 nucleocytoplasmic translocation and rpS6 activation. However, LHX8 does not directly regulate members of the PI3K-AKT pathway; instead, we show that LHX8 represses Lin28a expression, a known regulator of mammalian metabolism and of the AKT/mTOR pathway. LHX8 can bind to the Lin28a promoter, and the depletion of Lin28a in Lhx8-deficient oocytes partially suppresses primordial oocyte activation. Moreover, unlike the PI3K-AKT pathway, LHX8 is critical beyond primordial follicle activation, and blocks the primary to secondary follicle transition. Conclusions: Our results indicate that the LHX8-LIN28A pathway is essential in the earliest stages of primordial follicle activation, and LHX8 is an important oocyte-specific transcription factor in the ovary for regulating postnatal folliculogenesis

The Safe Use of a PTEN Inhibitor for the Activation of Dormant Mouse Primordial Follicles and Generation of Fertilizable Eggs

Primordial ovarian follicles, which are often present in the ovaries of premature ovarian failure (POF) patients or are cryopreserved from the ovaries of young cancer patients who are undergoing gonadotoxic anticancer therapies, cannot be used to generate mature oocytes for in vitro fertilization (IVF). There has been very little success in triggering growth of primordial follicles to obtain fertilizable oocytes due to the poor understanding of the biology of primordial follicle activation.We have recently reported that PTEN (phosphatase and tensin homolog deleted on chromosome ten) prevents primordial follicle activation in mice, and deletion of Pten from the oocytes of primordial follicles leads to follicular activation. Consequently, the PTEN inhibitor has been successfully used in vitro to activate primordial follicles in both mouse and human ovaries. These results suggest that PTEN inhibitors could be used in ovarian culture medium to trigger the activation of primordial follicle. To study the safety and efficacy of the use of such inhibitors, we activated primordial follicles from neonatal mouse ovaries by transient treatment with a PTEN inhibitor bpV(HOpic). These ovaries were then transplanted under the kidney capsules of recipient mice to generate mature oocytes. The mature oocytes were fertilized in vitro and progeny mice were obtained after embryo transfer.Long-term monitoring up to the second generation of progeny mice showed that the mice were reproductively active and were free from any overt signs or symptoms of chronic illnesses. Our results indicate that the use of PTEN inhibitors could be a safe and effective way of generating mature human oocytes for use in novel IVF techniques

Total Electron Temperature Derived from Quasi-Thermal Noise Spectroscopy In the Pristine Solar Wind: Parker Solar Probe Observations

The Quasi-thermal noise (QTN) technique is a reliable tool to yield accurate measurements of the electron parameters in the solar wind. We apply this method on Parker Solar Probe (PSP) observations to derive the total electron temperature ($T_e$) from the linear fit of the high-frequency part of the QTN spectra acquired by the RFS/FIELDS instrument, and present a combination of 12-day period of observations around each perihelion from Encounter One (E01) to Ten (E10) (with E08 not included) with the heliocentric distance varying from about 13 to 60 solar radii ($R_\odot{}$). We find that the total electron temperature decreases with the distance as $\sim$$R^{-0.66}$, which is much slower than adiabatic. The extrapolated $T_e$ based on PSP observations is consistent with the exospheric solar wind model prediction at $\sim$10 $R_\odot{}$, Helios observations at $\sim$0.3 AU and Wind observations at 1 AU. Also, $T_e$, extrapolated back to 10 $R_\odot{}$, is almost the same as the strahl electron temperature $T_s$ (measured by SPAN-E) which is considered to be closely related to or even almost equal to the coronal electron temperature. Furthermore, the radial $T_e$ profiles in the slower solar wind (or flux tube with larger mass flux) are steeper than those in the faster solar wind (or flux tube with smaller mass flux). More pronounced anticorrelated $V_p$-$T_e$ is observed when the solar wind is slower and closer to the Sun.Comment: 10 pages, 7 figures, and Astronomy & Astrophysics Accepte