A direct healthcare cost analysis of recombinant LH versus hMG supplementation on FSH during controlled ovarian hyperstimulation in the GnRH-antagonist protocol.

PURPOSE: We have previously published a retrospective matched-case control study comparing the effect of recombinant LH (r-hLH) versus highly purified human menopausal gonadotropin (hMG) supplementation on the follicle-stimulating hormone (FSH) during controlled ovarian hyperstimulation (COH) in the GnRH-antagonist protocol. The result from that study showed that the cumulative live birth rate (CLBR) was significantly higher in the r-hLH group (53% vs. 64%, p = 0.02). In this study, we aim to do a cost analysis between these two groups based on our previous study. METHODS: The analysis consisted of 425 IVF and ICSI cycles in our previous study. There were 259 cycles in the r-hFSH + hMG group and 166 cycles in the r-hFSH + r-hLH group. The total cost related to the treatment of each patient was recorded. Probabilistic sensitivity analysis (PSA) and a cost-effectiveness acceptability curve (CEAC) were performed and created. RESULTS: The total treatment cost per patient was significantly higher in the r-hFSH + r-hLH group than in the r-hFSH + hMG group ($4550 ± 798.86 vs. $4290 ± 734.6, p = 0.003). However, the mean cost per live birth in the r-hFSH + hMG group was higher at $8052, vs. $7059 in the r-hFSH + r-hLH group. The CEAC showed that treatment with hFSH + r-hLH proved to be more cost-effective than treatment with r-hFSH + hMG. Willingness-to-pay was evident when considering a hypothetical threshold of $18,513, with the r-hFSH + r-hLH group exhibiting a 99% probability of being considered cost-effective. CONCLUSION: The cost analysis showed that recombinant LH is more cost-effective than hMG supplementation on r-hFSH during COH in the GnRH-antagonist protocol.

Interleukin-1ß triggers muscle-derived extracellular superoxide dismutase expression and protects muscles from doxorubicin-induced atrophy.

Doxorubicin, a conventional chemotherapeutic agent prescribed for cancer, causes skeletal muscle atrophy and adversely affects mobility and strength. Given that doxorubicin-induced muscle atrophy is attributable primarily to oxidative stress, its effects could be mitigated by antioxidant-focused therapies; however, these protective therapeutic targets remain ambiguous. The aim of this study was to demonstrate that doxorubicin triggers severe muscle atrophy via upregulation of oxidative stress (4-hydroxynonenal and malondialdehyde) and atrogenes (atrogin-1/MAFbx and muscle RING finger-1) in association with decreased expression of the antioxidant enzyme extracellular superoxide dismutase (EcSOD), in cultured C2C12 myotubes and mouse skeletal muscle. Supplementation with EcSOD recombinant protein elevated EcSOD levels on the cellular membrane of cultured myotubes, consequently inhibiting doxorubicin-induced oxidative stress and myotube atrophy. Furthermore, doxorubicin treatment reduced interleukin-1ß (IL-1ß) mRNA expression in cultured myotubes and skeletal muscle, whereas transient IL-1ß treatment increased EcSOD protein expression on the myotube membrane. Notably, transient IL-1ß treatment of cultured myotubes and local administration in mouse skeletal muscle attenuated doxorubicin-induced muscle atrophy, which was associated with increased EcSOD expression. Collectively, these findings reveal that the regulation of skeletal muscle EcSOD via maintenance of IL-1ß signalling is a potential therapeutic approach to counteract the muscle atrophy mediated by doxorubicin and oxidative stress. KEY POINTS: Doxorubicin, a commonly prescribed chemotherapeutic agent for patients with cancer, induces severe muscle atrophy owing to increased expression of oxidative stress; however, protective therapeutic targets are poorly understood. Doxorubicin induced muscle atrophy owing to increased expression of oxidative stress and atrogenes in association with decreased protein expression of extracellular superoxide dismutase (EcSOD) in cultured C2C12 myotubes and mouse skeletal muscle. Supplementation with EcSOD recombinant protein increased EcSOD levels on the cellular membrane of cultured myotubes, resulting in inhibition of doxorubicin-induced oxidative stress and myotube atrophy. Doxorubicin treatment decreased interleukin-1ß (IL-1ß) expression in cultured myotubes and skeletal muscle, whereas transient IL-1ß treatment in vivo and in vitro increased EcSOD protein expression and attenuated doxorubicin-induced muscle atrophy. These findings reveal that regulation of skeletal muscle EcSOD via maintenance of IL-1ß signalling is a possible therapeutic approach for muscle atrophy mediated by doxorubicin and oxidative stress.

Systemic Diclofenac Sodium Reduces Postoperative rhBMP-2 Induced Neuroinflammation: A Rodent Model Study.

STUDY DESIGN: This is a basic science, animal research study. OBJECTIVE: This study aims to explore, in rodent models, the effectiveness of systemic nonsteroidal anti-inflammatory drugs in reducing recombinant human bone morphogenetic protein-2 (rhBMP-2) induced neuroinflammation. SUMMARY OF BACKGROUND DATA: rhBMP-2 is increasingly used to augment fusion in lumbar interbody fusion surgeries, although it can cause complications including postoperative radiculitis. MATERIALS AND METHODS: Eighteen 8-week-old Sprague-Dawley rats underwent Hargreaves testing to measure the baseline thermal withdrawal threshold before undergoing surgical intervention. The L5 nerve root was exposed and wrapped with an Absorbable Collagen Sponge containing rhBMP-2. Rats were randomized into 3 groups: (1) Low dose (LD), (2) high dose (HD) diclofenac sodium, and (3) saline, receiving daily injection treatment. Hargreaves testing was performed postoperatively on days 5 and 7. Seroma volumes were measured by aspiration and the nerve root was then harvested for hematoxylin and eosin, immunohistochemistry, Luxol Fast Blue staining, and real-time quantitative polymerase chain reaction. The Student t test was used to evaluate the statistical significance among groups. RESULTS: The intervention groups showed reduced seroma volume, and a general reduction of inflammatory markers (MMP12, MAPK6, GFAP, CD68, and IL18) compared with controls, with the reduction in MMP12 being statistically significant ( P = 0.02). Hematoxylin and eosin and immunohistochemistry of the nerve roots showed the highest macrophage density in the saline controls and the lowest in the HD group. Luxol Fast Blue staining showed the greatest extent of demyelination in the LD and saline groups. Lastly, Hargreaves testing, a functional measure of neuroinflammation, of the HD group demonstrated a minimal change in thermal withdrawal latency. In contrast, the thermal withdrawal latency of the LD and saline groups showed a statistically significant decrease of 35.2% and 28.0%, respectively ( P < 0.05). CONCLUSION: This is the first proof-of-concept study indicating that diclofenac sodium is effective in alleviating rhBMP-2-induced neuroinflammation. This can potentially impact the clinical management of rhBMP-2-induced radiculitis. It also presents a viable rodent model for evaluating the effectiveness of analgesics in reducing rhBMP-2-induced inflammation.

[Clinical observation of Qiliqiangxin capsule combined with recombinant human brain natriuretic peptide in patients with acute heart failure].

Objective: To observe the clinical effect of Qiliqiangxin capsule combined with recombinant human brain natriuretic peptide in acute left heart failure patients 7 days after onset as well as the effects of plasma MDA and ET-1. Methods: In total, 240 hospitalized patients with acute left heart failure from October 2017 to May 2021 were selected from the Department of Emergency and Critical Care Center of Beijing Anzhen Hospital, Capital Medical University and the Department of Cardiology of the Jilin Provincial People's Hospital. They were randomly divided into routine treatment group and combined treatment group, with 120 cases in each group. The routine treatment group was treated with vasodilation, diuresis, cardiotonic and recombinant human brain natriuretic peptide. The combined treatment group was treated with Qiliqiangxin capsules based on the routine treatment group. One week later, the changes in clinical efficacy, ejection fraction, left ventricular commoid diameter, and plasma BNP, MDA, and ET-1 were compared between the two groups before and after treatment. SPSS 11.5 statistical software was used. The measurement data was expressed in x¯±s, the independent sample t-test was used for comparison between groups, and the paired t-test was used for comparison before and after treatment within groups. Counting data was expressed as case (%), and the rank sum test was used for inter-group comparison. Result: In terms of clinical efficacy, the total effective rate of the combined treatment group was significantly higher than that of the conventional treatment group, and the difference was statistically significant (P<0.05). Compared with the routine treatment group, the left ventricular ejection fraction in the combined treatment group was significantly increased (P<0.05). The levels of plasma BNP, MDA and ET-1 were significantly decreased (P<0.05). Conclusion: Qiliqiangxin capsule combined with rhBNP treatment can effectively improve the clinical symptoms of acute heart failure, as well as reduce the lipid peroxidation product MDA content and endothetin ET-1 level in blood. The clinical application value of the Qiliqiangxin capsule needs to be further confirmed by further trials.

Recombinant or endogenous thyroid-stimulating hormone for radioactive iodine therapy in thyroid cancer: state of knowledge and current controversies.

For patients undergoing radioiodine therapy (RIT) of differentiated thyroid carcinoma (DTC), thyroid-stimulating hormone (TSH) stimulation prior to RIT can be achieved using thyroid hormone withdrawal (THW) or administration of recombinant human TSH (rhTSH). As THW can lead to nausea, headaches, vomiting, fatigue, and dizziness secondary to transient acute hypothyroidism, rhTSH could be a good alternative. Recombinant human TSH has been administered in patients in order to stimulate TSH for RIT since 2005. According to the Martinique criteria formulated by the leading professional societies involved in care of patients with DTC, rhTSH can be applied in 3 settings: for remnant ablation, adjuvant treatment, and treatment of known disease. Numerous studies have investigated the effects of rhTSH as a method of TSH stimulation on the thyroid cell, the systemic effects, biokinetics, and clinical outcomes; however, no consensus has been reached about many aspects of its potential use. Recombinant human TSH is able to stimulate sufficient TSH levels (>30 mIU L-1) and is hypothesized to decrease risks of tumor cell proliferation. As rhTSH-use avoids the transiently impaired renal function associated with THW, radioiodine excretion is faster with the former, leading to a lower iodine-131 uptake and a difference in fractional remnant uptake, effective half-life, mean residence time, and dose to the blood. Differences between rhTSH and THW were observed in radioiodine genotoxic effects and endothelial-dependent vasodilation and inflammation. For thyroid remnant ablation, THW and rhTSH lead to similar remnant ablation rates. For adjuvant therapy and treatment of known disease, insufficient trials have been conducted and future prospective studies are recommended. The current review provides a state-of-the-science overview on the issues and debates surrounding TSH stimulation through either rhTSH adminsitration orendogenous TSH production after levothyroxin withdrawal.

Cost comparison of filgrastim versus pegfilgrastim and pegfilgrastim biosimilars for inpatient prophylaxis of febrile neutropenia.

INTRODUCTION: The Ohio State University Comprehensive Cancer Center (The James) uses daily subcutaneous filgrastim as the inpatient granulocyte colony-stimulating factor of choice. The coordination of care associated with filgrastim can often be a barrier to patient discharge. The purpose of this study was to compare the inpatient cost of daily filgrastim to single dose pegfilgrastim and biosimilars. METHODS: Adult patients admitted to The James who received at least one dose of filgrastim between June 1, 2021 and August 31, 2021 were retrospectively identified. This study compared the inpatient cost of filgrastim and biosimilars associated with one chemotherapy cycle to the potential inpatient cost of pegfilgrastim and biosimilars based on average sales price (ASP). Additionally, the number and duration of discharge prescriptions for filgrastim was determined. RESULTS: Of the 44 unique patient encounters that met inclusion criteria, 19 received 300-mcg doses of filgrastim and 25 received 480-mcg doses. The median number of doses administered per admission was eight. If each of these patients were to instead receive the most inexpensive biosimilar, pegfilgrastim reference product, the cost would be 216% higher than with filgrastim-sndz. At discharge, 15 patients (34%) received a prescription for filgrastim to be continued for a median duration of 6 days. CONCLUSION: Based on ASP, pegfilgrastim was more costly than filgrastim. Potential rebates and negotiation power may alter the financial outlook of adding pegfilgrastim to inpatient formulary. Exploration of delays in discharge due to insurance coordination for filgrastim continuation in the outpatient setting may also impact formulary decisions.

Efficacy and safety of topical 5-fluorouracil in conjunctival intraepithelial neoplasia refractory to interferon alpha-2b.

PURPOSE: To report the efficacy and safety of 5-fluorouracil as the second line of treatment for two cases of conjunctival intraepithelial neoplasia refractive to topical interferon alpha-2b. CASE REPORT: In the first case, a 77-year-old woman was evaluated because of a fleshy vascularized lesion in the temporal conjunctiva on her right eye with leukoplakia of the corneal epithelium from 10- to 5-o'clock limbus. In the second case, an 81-year-old man, a nodular lesion in the temporal conjunctiva on his RE, with corneal adjacent opalescence, one millimeter in extent, was observed. Both patients were initially treated with excisional surgery, the samples being reported as conjunctival intraepithelial neoplasia with high-grade dysplasia. Co-adjuvant treatment with topical interferon alpha-2b 1 mIU/mL was indicated 4 times/day uninterruptedly. In the first case, there was no response despite 8 months of treatment, while in the second, the corneal lesion progressed in an arboriform pattern after 4 months of topical chemotherapy. MANAGEMENT & OUTCOME: In the absence of efficacy, the treatment was then changed to topical 5-fluorouracil (1%), 4 times/day for 7 days with a time-lapse of 21 days off, which constitutes a course. Two and four courses of treatment with 5-fluorouracil 1% were completed in both cases in the absence of important side effects. After the first course, both patients showed complete remission of the lesions. No clinical signs of relapse were noted after 1 year of follow-up. DISCUSSION: The treatment with 5-fluorouracil is a good option as the second line of treatment for conjunctival intraepithelial neoplasia who are low-responders to interferon alpha-2b, with fewer side effects than other currently available alternatives.

Clinical observation of Qiliqiangxin capsule combined with recombinant human brain natriuretic peptide in patients with acute heart failure / 中华内科杂志

Objective: To observe the clinical effect of Qiliqiangxin capsule combined with recombinant human brain natriuretic peptide in acute left heart failure patients 7 days after onset as well as the effects of plasma MDA and ET-1. Methods: In total, 240 hospitalized patients with acute left heart failure from October 2017 to May 2021 were selected from the Department of Emergency and Critical Care Center of Beijing Anzhen Hospital, Capital Medical University and the Department of Cardiology of the Jilin Provincial People's Hospital. They were randomly divided into routine treatment group and combined treatment group, with 120 cases in each group. The routine treatment group was treated with vasodilation, diuresis, cardiotonic and recombinant human brain natriuretic peptide. The combined treatment group was treated with Qiliqiangxin capsules based on the routine treatment group. One week later, the changes in clinical efficacy, ejection fraction, left ventricular commoid diameter, and plasma BNP, MDA, and ET-1 were compared between the two groups before and after treatment. SPSS 11.5 statistical software was used. The measurement data was expressed in x¯±s, the independent sample t-test was used for comparison between groups, and the paired t-test was used for comparison before and after treatment within groups. Counting data was expressed as case (%), and the rank sum test was used for inter-group comparison. Result: In terms of clinical efficacy, the total effective rate of the combined treatment group was significantly higher than that of the conventional treatment group, and the difference was statistically significant (P<0.05). Compared with the routine treatment group, the left ventricular ejection fraction in the combined treatment group was significantly increased (P<0.05). The levels of plasma BNP, MDA and ET-1 were significantly decreased (P<0.05). Conclusion: Qiliqiangxin capsule combined with rhBNP treatment can effectively improve the clinical symptoms of acute heart failure, as well as reduce the lipid peroxidation product MDA content and endothetin ET-1 level in blood. The clinical application value of the Qiliqiangxin capsule needs to be further confirmed by further trials.

Production of recombinant and therapeutic proteins in microalgae.

Microalgae is emerging as a promising platform for the production of recombinant proteins of therapeutic importance. Since microalgae are safe for oral consumption and some microalgal species can form extracellular vesicles, they can potentially be used as edible vaccines or drug-delivery vehicles in addition to their status as naturally rich sources of nutraceutical bioproducts. This article focuses on recent advances in the field of recombinant protein production in microalgae, and developments toward the use of microalgae as a vehicle for drug delivery.

Granulocyte colony stimulating factor use and adherence to clinical practice guidelines among women with breast cancer living in Puerto Rico: a population-based study.

BACKGROUND: Febrile Neutropenia (FN) is a common and serious condition related to cancer chemotherapy. Human recombinant Granulocyte-Colony Stimulating Factor (G-CSF) prevents and attenuates the severity and duration of FN. We evaluated the use and predictors of G-CSF adherence among women with breast cancer with a high risk of FN in Puerto Rico. METHODS: This retrospective cohort study used the Puerto Rico Central Cancer Registry-Health Insurance Linkage Database. Women with invasive breast cancer diagnosed during 2009-2015 who received selected chemotherapy regimens (n = 816) were included. The risk of FN was categorized as high and low risk based on the chemotherapy regimens according to the National Comprehensive Cancer Network guidelines and literature. Adherence was defined as the use or no use of G-CSF at the start of the first chemotherapy cycle among women with breast cancer based on the risk of developing FN. We used a multivariate logistic model to identify factors associated with G-CSF use in women classified at high risk for FN. RESULTS: Adherence to G-CSF clinical practice guidelines was low (38.2%) among women with a high risk of FN. Women at high risk of FN with Medicaid (aOR: 0.14; CI 95%: 0.08, 0.24) and Medicare/Medicaid (aOR: 0.33; CI 95%: 0.15, 0.73) were less likely to receive G-CSF than women with private health insurance. Women with regional stage (aOR: 1.82; CI 95%: 1.15, 2.88) were more likely to receive G-CSF than women with localized cancers. CONCLUSIONS: Adherence to clinical practice guidelines was poor among women with a high risk of FN. Furthermore, disparities in the adherence to G-CSF use in terms of health insurance, health region, and cancer stage granted the opportunity to implement strategies to follow the recommended guidelines for using G-CSF as part of cancer treatment.

Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia.

There has been increasing research momentum to identify new therapeutic agents for the prevention or treatment of preeclampsia, drugs that can affect the underlying disease pathophysiology. Molecular targets of candidate treatments include oxidative stress, antiangiogenic factors, and the angiotensin, nitric oxide, and proinflammatory pathways. The proposed treatments undergoing preclinical and clinical trial evaluation are thought to act on placental or endothelial disease or both. Most have adopted the pragmatic strategy of repurposing drugs. Of all the therapeutic agents proposed, pravastatin has received the most interest. There are preclinical studies showing that it has pleiotropic actions that favorably impact on multiple molecular targets and can resolve a preeclampsia phenotype in many animal models. An early phase clinical trial suggests that it may have therapeutic activity. Several large prevention trials are planned or ongoing and, when completed, could definitively address whether pravastatin can prevent preeclampsia. Proton-pump inhibitors, metformin, and sulfasalazine are other drugs with preclinical evidence of multiple molecular actions that could resolve the pathophysiology of preeclampsia. These agents are also currently being evaluated in clinical trials. There have been many recent preclinical studies identifying the potential of numerous natural compounds to treat preeclampsia, such as plant extracts and micronutrients that have potent anti-inflammatory or antioxidant activity. Recent preclinical studies have also proposed novel molecular-targeted strategies, such as monoclonal antibodies targeting tumor necrosis factor alpha, placental growth factor, and short interfering RNA technology, to silence the gene expression of soluble fms-like tyrosine kinase-1 or angiotensinogen. Other treatment approaches that have transitioned to human trials (ranging from single-arm to phase III trials that have been completed or are ongoing) include folic acid, nitric oxide donors (such as L-arginine), recombinant antithrombin III, digoxin immune antigen-binding fragment, and melatonin. There have been case series showing the removal of circulating soluble fms-like tyrosine kinase-1 may help stabilize the disease and prolong pregnancy. Interestingly, there are case reports suggesting that monoclonal antibody eculizumab (complement inhibitor) may have therapeutic potential. If new agents are discovered that are proven to be effective in preventing or treating preeclampsia, the potential to improve global maternal and perinatal health will be significant.

Preliminary Investigation of Microbiome and Dietary Differences in Patients with Phenylketonuria on Enzyme Substitution Therapy Compared to Traditional Therapies.

BACKGROUND: Phenylketonuria (PKU) is an inborn error of metabolism that impairs the function of the enzyme phenylalanine hydroxylase. Historical treatment includes limiting dietary phenylalanine (Phe) consumption while supplementing with medical food; however, this treatment has been associated with complications, such as nutritional deficiencies and disruptions in the gut microbiota. OBJECTIVE: The study aim was to compare dietary and gut microbiome differences between adult patients on a traditional PKU diet with those receiving the enzyme substitution therapy Palynziq on a liberalized diet while controlling blood Phe levels to <600 µmol/L (to convert to mg/dL divide by 60.5). DESIGN: A cross-sectional study was conducted comparing patients on a traditional Phe-restricted diet with patients receiving Palynziq eating a liberalized diet. PARTICIPANTS/SETTING: Six patients eating a traditional Phe-restricted diet with medical food and 6 patients on Palynziq eating a liberalized diet without medical food intake for more than 3 years were selected from the University of Kentucky Metabolic Clinic from August to December 2019. MAIN OUTCOME MEASURES: Nutrient intake from 3-day diet records and fecal microbiome taxonomic abundances were analyzed. STATISTICAL ANALYSIS: Mann-Whitney U tests were used for dietary data analysis. Differential abundance analysis for microbiome taxa and pathway data was done using DESeq2 analysis. RESULTS: Dietary data showed patients receiving Palynziq consumed a lower percent of kilocalories from total protein and lower amounts of most micronutrients, but consumed greater amounts of intact protein and cholesterol (P < .05). Microbiome data revealed a greater abundance of the phylum Verrucomicrobia and genus Lachnobacterium in the Traditional group and a greater abundance of the genus Prevotella in the Palynziq group (P < .05). Pathway analysis depicted greater enrichment in carotenoid and amino acid metabolism pathways in the Traditional group (P < .05). Protein (% kcal), dietary fiber (g), fat (% kcal), linolenic acid (% Dietary Reference Intakes), and age were correlated with the underlying microbial community structure for both groups combined. CONCLUSIONS: Patients with PKU treated with Palynziq on a liberalized diet manifest significant differences in diet composition compared with those treated with traditional Phe-restricted diets. Several of these dietary differences may affect the microbiome architecture.

Evaluation of recombinant human erythropoietin responsiveness by measuring erythrocyte creatine content in haemodialysis patients.

BACKGROUND: One of the main causes of anaemia in patients with end-stage renal disease is relative deficiency in erythropoietin production. Eythropoiesis stimulating agent (ESA), a potent haematopoietic growth factor, is used to treat anaemia in haemodialysis patients. The effect of ESA is usually assessed by haematological indices such as red blood cell count, haemoglobin concentration and haematocrit, but erythrocyte indices do not provide information of the rapid change in erythropoietic activity. As erythrocyte creatine directly assess erythropoiesis, the aim of this study was to evaluate the effect of ESA in haemodialysis patients by measuring the erythrocyte creatine content. METHODS: ESA dose was fixed 3 months prior to the enrollment and was maintained throughout the entire study period. Erythrocyte creatine was measured with haematologic indices in 83 haemodialysis patients. Haemoglobin was also measured 3 months after. RESULTS: ESA dose (152.4 ± 62.9 vs. 82.2 ± 45.5 units/kg/week, P = 0.0001) and erythrocyte creatine (2.07 ± 0.73 vs. 1.60 ± 0.41 µmol/gHb, p = 0.0003) were significantly higher in 27 patients with haemoglobin <10 g/dL compared to 56 patients with haemoglobin ≥10 g/dL. There was a fair correlation between ESA dose and the concentration of creatine in the erythrocytes (r = 0.55, P < 0.0001). Increase in haemoglobin (>0.1 g/dL) was observed in 37 patients, whereas haemoglobin did not increase in 46 patients. Erythrocyte creatine levels were significantly higher in those patients with an increase in haemoglobin compared to those without (2.04 ± 0.64 vs. 1.52 ± 0.39 µmol/gHb, p < 0.0001). When 8 variables (ESA dose, erythropoietin resistance index, C-reactive protein, intact parathyroid hormone, iron supplementation, presence of anaemia, erythrocyte creatine and reticulocyte) were used in the multivariate logistic analysis, erythrocyte creatine levels emerged as the most important variable associated with increase in haemoglobin (Chi-square = 6.19, P = 0.01). CONCLUSION: Erythrocyte creatine, a useful marker of erythropoietic capacity, is a reliable marker to estimate ameliorative effectiveness of ESA in haemodialysis patients.

Recombinant Human HPS Protects Mice and Nonhuman Primates from Acute Liver Injury.

Acute liver injury shares a common feature of hepatocytes death, immune system disorders, and cellular stress. Hepassocin (HPS) is a hepatokine that has ability to promote hepatocytes proliferation and to protect rats from D-galactose (D-Gal)- or carbon tetrachloride (CCl4)-induced liver injury by stimulating hepatocytes proliferation and preventing the high mortality rate, hepatocyte death, and hepatic inflammation. In this paper, we generated a pharmaceutical-grade recombinant human HPS using mammalian cells expression system and evaluated the effects of HPS administration on the pathogenesis of acute liver injury in monkey and mice. In the model mice of D-galactosamine (D-GalN) plus lipopolysaccharide (LPS)-induced liver injury, HPS treatment significantly reduced hepatocyte death and inflammation response, and consequently attenuated the development of acute liver failure. In the model monkey of D-GalN-induced liver injury, HPS administration promoted hepatocytes proliferation, prevented hepatocyte apoptosis and oxidation stress, and resulted in amelioration of liver injury. Furthermore, the primary pharmacokinetic study showed natural HPS possesses favorable pharmacokinetics; the acute toxicity study indicated no significant changes in behavioral, clinical, or histopathological parameters of HPS-treated mice, implying the clinical potential of HPS. Our results suggest that exogenous HPS has protective effects on acute liver injury in both mice and monkeys. HPS or HPS analogues and mimetics may provide novel drugs for the treatment of acute liver injury.

Biotechnology-based therapeutics for management of cerebral stroke.

Cerebral stroke, commonly caused due to hindrance in blood flow, is broadly classified into two categories-ischemic and haemorrhagic strokes. The onset of stroke triggers multiple mechanisms causing inflammation, generation of free radicals and protein damage leading to apoptosis of neuronal cells. The current therapies available for cerebral strokes involve use of complex surgical treatments and tissue plasminogen activator which increases the risk of internal bleeding, brain edema and cerebral damage, thereby restricting their use in clinical setting. The alarming need to develop safe, effective, target specific systems which, promote neuronal growth and reduce cerebral inflammation can be accomplished with use of biotechnological approaches. The article gives an insight to biotechnology-based advancements for tissue plasminogen activators, cell penetrating peptides, growth factors, ribonucleic acid systems and monoclonal antibodies for cerebral stroke. We also emphasis on challenges and future perspective of biotechnology-based therapeutics for better management of stroke.

Biological Therapies in the Treatment of Cancer-Update and New Directions.

Biological therapies have changed the face of oncology by targeting cancerous cells while reducing the effect on normal tissue. This publication focuses mainly on new therapies that have contributed to the advances in treatment of certain malignancies. Immunotherapy, which has repeatedly proven to be a breakthrough therapy in melanoma, as well as B-ALL therapy with CAR T cells, are of great merit in this progress. These therapies are currently being developed by modifying bispecific antibodies and CAR T cells to improve their efficiency and bioavailability. Work on improving the therapy with oncolytic viruses is also progressing, and efforts are being made to improve the immunogenicity and stability of cancer vaccines. Combining various biological therapies, immunotherapy with oncolytic viruses or cancer vaccines is gaining importance in cancer therapy. New therapeutic targets are intensively sought among neoantigens, which are not immunocompromised, or antigens associated with tumor stroma cells. An example is fibroblast activation protein α (FAPα), the overexpression of which is observed in the case of tumor progression. Universal therapeutic targets are also sought, such as the neurotrophic receptor tyrosine kinase (NTRK) gene fusion, a key genetic driver present in many types of cancer. This review also raises the problem of the tumor microenvironment. Stromal cells can protect tumor cells from chemotherapy and contribute to relapse and progression. This publication also addresses the problem of cancer stem cells resistance to treatment and presents attempts to avoid this phenomenon. This review focuses on the most important strategies used to improve the selectivity of biological therapies.

Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: An Integrated Analysis of Preclinical and Clinical Data.

Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood-brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.

Nutrition status of adults with phenylketonuria treated with pegvaliase.

BACKGROUND: Pegvaliase is an enzyme substitution therapy that reduces blood phenylalanine (Phe) in adults with phenylketonuria (PKU), and often allows normalization of protein intake (≥0.8 g protein/kg). Here we examine the nutrition status of adults with PKU consuming a normal protein intake without medical food after being treated with pegvaliase for ≥1 year. METHODS: A cross-sectional study evaluating nutritional intake (3-day food record and food frequency questionnaire), anthropometrics, laboratory indices of protein, micronutrient, and essential fatty acid (EFA) status, and questionnaires evaluating food neophobia and Epicurean eating pleasure. RESULTS: Participants (n = 18, 61% female) started pegvaliase 4.9 ± 2.1 years prior to enrollment and were aged 38.2 ± 8.8 years with a mean BMI of 29.2 ± 4.1 kg/m2. Participants consumed a mean of 73.2 ± 17.6 g protein/d (1.0 ± 0.3 g/kg/d). Eleven participants had low blood Phe (<30 µmol/L) with adequate protein intake and normal indices of protein status. Micronutrient and EFA concentrations were normal except for mildly low vitamin D (<30 ng/mL, n = 12). Intakes of sodium, saturated fat, and added sugars exceeded recommendations for healthy adults, though mean diet quality was comparable to a US adult reference population. Lower food neophobia scores correlated with an increased aesthetic appreciation of food. However, 53% of participants self-reported having moderate (n = 6) to high (n = 3) food neophobia. DISCUSSION: Participants treated with pegvaliase consumed an unrestricted diet with adequate dietary protein and, overall, had normal protein, micronutrient, and fatty acid status. Despite low blood Phe, protein nutriture was not compromised. While nutritional deficiencies were not identified, diet quality was suboptimal and some participants reported food neophobia. Nutrition education remains an important component of care as patients adapt to a normal diet.

Gene therapy for hemophilia B using CB 2679d-GT: a novel factor IX variant with higher potency than factor IX Padua.

Sustained expression of therapeutic factor IX (FIX) levels has been achieved after adeno-associated viral (AAV) vector-based gene therapy in patients with hemophilia B. Nevertheless, patients are still at risk of vector dose-limiting toxicity, particularly liver inflammation, justifying the need for more efficient vectors and a lower dosing regimen. A novel increased potency FIX (designated as CB 2679d-GT), containing 3 amino acid substitutions (R318Y, R338E, T343R), significantly outperformed the R338L-Padua variant after gene therapy. CB 2679d-GT demonstrated a statistically significant approximately threefold improvement in clotting activity when compared with R338L-Padua after AAV-based gene therapy in hemophilic mice. Moreover, CB 2679d-GT gene therapy showed significantly reduced bleeding time (approximately fivefold to eightfold) and total blood loss volume (approximately fourfold) compared with mice treated with the R338L-Padua, thus achieving more rapid and robust hemostatic correction. FIX expression was sustained for at least 20 weeks with both CB 2679d-GT and R338L-Padua whereas immunogenicity was not significantly increased. This is a novel gene therapy study demonstrating the superiority of CB 2679d-GT, highlighting its potential to obtain higher FIX activity levels and superior hemostatic efficacy following AAV-directed gene therapy in hemophilia B patients than what is currently achievable with the R338L-Padua variant.