Cellular and Molecular Alterations Underlying Abnormal Bone Growth in X-Linked Hypophosphatemia

X-linked hypophosphatemia (XLH), the most common form of hereditary hypophosphatemic rickets, is caused by inactivating mutations of the phosphate-regulating endopeptidase gene (PHEX). XLH is mainly characterized by short stature, bone deformities and rickets, while in hypophosphatemia, normal or low vitamin D levels and low renal phosphate reabsorption are the principal biochemical aspects. The cause of growth impairment in patients with XLH is not completely understood yet, thus making the study of the growth plate (GP) alterations necessary. New treatment strategies targeting FGF23 have shown promising results in normalizing the growth velocity and improving the skeletal effects of XLH patients. However, further studies are necessary to evaluate how this treatment affects the GP as well as its long-term effects and the impact on adult height.

Download Full-text

Is Host Metabolism the Missing Link to Improving Cancer Outcomes?

Cancers ◽

10.3390/cancers12092338 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2338

Author(s):

Christopher M. Wright ◽

Anuradha A. Shastri ◽

Emily Bongiorno ◽

Ajay Palagani ◽

Ulrich Rodeck ◽

...

Keyword(s):

Metabolic Syndrome ◽

Tumor Cells ◽

Treatment Options ◽

Detailed Knowledge ◽

Pharmacological Agents ◽

Molecular Alterations ◽

Number Of Patients ◽

Disease Site ◽

New Treatment ◽

The Impact

For the past 100 years, oncologists have relentlessly pursued the destruction of tumor cells by surgical, chemotherapeutic or radiation oncological means. Consistent with this focus, treatment plans are typically based on key characteristics of the tumor itself such as disease site, histology and staging based on local, regional and systemic dissemination. Precision medicine is similarly built on the premise that detailed knowledge of molecular alterations of tumor cells themselves enables better and more effective tumor cell destruction. Recently, host factors within the tumor microenvironment including the vasculature and immune systems have been recognized as modifiers of disease progression and are being targeted for therapeutic gain. In this review, we argue that—to optimize the impact of old and new treatment options—we need to take account of an epidemic that occurs independently of—but has major impact on—the development and treatment of malignant diseases. This is the rapidly increasing number of patients with excess weight and its’ attendant metabolic consequences, commonly described as metabolic syndrome. It is well established that patients with altered metabolism manifesting as obesity, metabolic syndrome and chronic inflammation have an increased incidence of cancer. Here, we focus on evidence that these patients also respond differently to cancer therapy including radiation and provide a perspective how exercise, diet or pharmacological agents may be harnessed to improve therapeutic responses in this patient population.

Download Full-text

Switching from conventional therapy to burosumab injection has the potential to prevent nephrocalcinosis in patients with X-linked hypophosphatemic rickets

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0734 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Daisuke Harada ◽

Kaoru Ueyama ◽

Kyoko Oriyama ◽

Yoshihito Ishiura ◽

Hiroko Kashiwagi ◽

...

Keyword(s):

Conventional Therapy ◽

Hypophosphatemic Rickets ◽

High Dose ◽

Normal Range ◽

Urine Calcium ◽

Metabolic Bone ◽

Renal Phosphate Reabsorption ◽

Before And After ◽

Fgf 23 ◽

The Impact

Abstract Objectives X-linked hypophosphatemic rickets (XLH) is a congenital fibroblast growth factor (FGF)23-related metabolic bone disease that is treated with active vitamin D and phosphate as conventional therapies. Complications of these therapies include nephrocalcinosis (NC) caused by excessive urine calcium and phosphate concentrations. Recently, an anti-FGF23 antibody, burosumab, was developed and reported to be effective in poorly-controlled or severe XLH patients. This study aimed to reveal the impact of switching treatments in relatively well-controlled XLH children with the Rickets Severity Scale less than 2.0. Methods The effects of the two treatments in eight relatively well-controlled XLH children with a mean age of 10.4 ± 1.9 years were compared retrospectively for the same treatment duration (31 ± 11 months) before and after the baseline. Results Actual doses of alfacalcidol and phosphate as conventional therapy were 150.9 ± 43.9 ng/kg and 27.5 ± 6.3 mg/kg per day, respectively. Renal echography revealed spotty NC in 8/8 patients, but no aggravation of NC was detected by switching treatments. Switching treatments increased TmP/GFR (p=0.002) and %TRP (p<0.001), and improved the high urine calcium/creatinine ratio to the normal range (p<0.001) although both treatments controlled disease markers equally. Additionally, low intact parathyroid hormone during conventional therapy was increased within the normal range by switching treatments. Conclusions Our results suggest that a high dose of alfacalcidol was needed to control the disease, but it caused hypercalciuria and NC. We concluded that switching treatments in relatively well-controlled XLH children improved renal phosphate reabsorption and decreased urine calcium extraction, and may have the potential to prevent NC.

Download Full-text

Progressive multifocal leukoencephalopathy: new concepts

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20130154 ◽

2013 ◽

Vol 71 (9B) ◽

pp. 699-702 ◽

Cited By ~ 13

Author(s):

Marco A. Lima

Keyword(s):

Progressive Multifocal Leukoencephalopathy ◽

Demyelinating Disease ◽

Jc Virus ◽

Treatment Strategies ◽

Antiretroviral Drugs ◽

Transplant Recipients ◽

New Concepts ◽

Immunosuppressive Medications ◽

New Treatment ◽

The Impact

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the CNS caused by reactivation of JC virus (JCV) in a setting of cellular immunosuppression. Originally, PML was observed in patients with advanced HIV infection, lymphoproliferative disorders and transplant recipients. However, the widespread use of HIV antiretroviral drugs and the new selective immunomodulatory and immunosuppressive medications, such as Rituximab and Natalizumab, has recently modified the epidemiology, clinical presentation and prognosis of PML. Herein, we discuss the new concepts on PML, emphasizing the recent modification in the epidemiology; the impact of new immunomodulatory treatments in the disease, PML-IRIS (Immune reconstitution inflammatory síndrome), new treatment strategies and other JCV related CNS diseases.

Download Full-text

HER2-Low Breast Cancer: Molecular Characteristics and Prognosis

Cancers ◽

10.3390/cancers13112824 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2824

Author(s):

Elisa Agostinetto ◽

Mattia Rediti ◽

Danai Fimereli ◽

Véronique Debien ◽

Martine Piccart ◽

...

Keyword(s):

Breast Cancer ◽

Treatment Strategies ◽

The Cancer Genome Atlas ◽

Survival Outcomes ◽

Molecular Characteristics ◽

Prognostic Impact ◽

Intrinsic Subtypes ◽

Free Interval ◽

New Treatment ◽

The Impact

Background: We aimed to determine the distribution of intrinsic subtypes within HER2-low breast cancer (BC), and to describe the prognostic impact of HER2-low status on survival outcomes. Methods: This is a retrospective, observational study of primary BC extracted from The Cancer Genome Atlas dataset. We described the distribution of PAM50 intrinsic subtypes within HER2-low BC subtype according to hormonal receptor status (positive (HR+) and negative (HR−)). Secondly, we assessed the impact of HER2-low on survival outcomes (progression-free interval (PFI), disease-free interval (DFI), and overall survival (OS)). Results: We analyzed 804 primary BCs, including 410 (51%) HER2-low BCs (336 HR+ and 74 HR−). The proportion of HER2-enriched tumors was higher in the HER2-low/HR− group compared to HER2-low/HR+ (13.7% versus 1.2%, respectively). HER2-enriched tumors were more frequent in HER2-low/HR− and HER2-low/HR+ subtypes, compared to HER2-negative/HR− and HER2-negative/HR+ subtypes, respectively (13.7% versus 1.6% and 1.2% versus 0.5%, respectively). We observed no significant differences in PFI, DFI, and OS between HER2-low subtypes and each non-HER2-low subtype paired by HR status. Conclusions: Our characterization of PAM50 intrinsic subtypes within HER2-low breast cancer may explain the different clinical behaviors and responses to treatment, and ultimately support further investigation of new treatment strategies in the HER2-low category. Moreover, it highlights the importance of considering HR status in the HER2-low category.

Download Full-text

FGF23-related hypophosphatemic rickets/osteomalacia: diagnosis and new treatment

Journal of Molecular Endocrinology ◽

10.1530/jme-20-0089 ◽

2020 ◽

Author(s):

Seiji Fukumoto

Keyword(s):

Vitamin D ◽

Human Monoclonal Antibody ◽

Complete Removal ◽

Hypophosphatemic Rickets ◽

Long Term Effects ◽

Novel Therapy ◽

First Choice ◽

Proximal Tubular ◽

New Treatment

FGF23 is a phosphaturic hormone produced by bone. FGF23 reduces serum phosphate by suppressing proximal tubular phosphate reabsorption and intestinal phosphate absorption. After the identification of FGF23, several kinds of hypophosphatemic rickets/osteomalacia such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO) have been shown to be caused by excessive actions of FGF23. Circulatory FGF23 is high in patients with these hypophosphatemic diseases while FGF23 is rather low in those with chronic hypophosphatemia from other causes such as vitamin D deficiency. These results indicate that FGF23 measurement is useful for the differential diagnosis of hypophosphatemia. Chemiluminescent enzyme immunoassay for FGF23 has been approved for clinical use in Japan. The first choice treatment for patients with TIO is complete removal of responsible tumors. However, it is not always possible to find and completely remove responsible tumors. Phosphate and active vitamin D have been used for patients with hypophosphatemic diseases caused by excessive actions of FGF23 including TIO patients with unresectable tumors. However, these medications have limited effects and several adverse events. The inhibition of excessive FGF23 actions has been considered to be a novel therapy for these hypophosphatemic diseases. Human monoclonal antibody for FGF23, burosumab, has been shown to improve biochemical abnormalities, roentgenological signs of rickets, growth, fracture healing and impaired mineralization in patients with XLH. Burosumab has been approved in several countries including Europe, North America and Japan. Long-term effects of burosumab need to be addressed in future studies.

Download Full-text

Treatment with antipsychotics: The impact on the patient in the community

European Psychiatry ◽

10.1016/s0924-9338(97)89491-6 ◽

1998 ◽

Vol 13 (S1) ◽

pp. 31s-36s ◽

Cited By ~ 1

Author(s):

W Rössler ◽

HJ Salize ◽

I Reinhard

Keyword(s):

Treatment Strategies ◽

Antipsychotic Agents ◽

Care Quality ◽

Conventional Antipsychotics ◽

Atypical Antipsychotic Agents ◽

Schizophrenic Patients ◽

New Treatment ◽

One Year ◽

The Impact

SummaryThe assessment of new treatment strategies such as the atypical antipsychotic agents goes far beyond the assessment of psychopathology, and includes evaluation of their effects on a variety of needs associated with living in the community. This article provides some empirical data for such a multidimensional perspective in analysing drug treatment with conventional antipsychotics. We focus on two groups of schizophrenic patients discharged from a psychiatric hospital, who were followed up for one year. One group was treated with oral and the other with depot medication. The two groups were assessed on their needs for care, quality of life, and rehospitalisation rates. We found few significant differences between depot- and orally-medicated patients. However, patients treated with depot antipsychotics were receiving higher mean daily doses. Patients taking oral medication had a lower rate of adverse effects but were more non-compliant, which resulted in a higher rehospitalisation rate, confirming our assumpt on that patients take different risk-to-benefit decisions. Orally-medicated patients did not have a better functional status than depot-medicated patients.

Download Full-text

Impact of a Transfusion-free Program on Patients Undergoing Pancreaticoduodenectomy

The American Surgeon ◽

10.1177/000313481608200217 ◽

2016 ◽

Vol 82 (2) ◽

pp. 140-145 ◽

Cited By ~ 2

Author(s):

Young Bae Jeon ◽

Sangchul Yun ◽

Si Young Ok ◽

Han Joon Kim ◽

Dongho Choi

Keyword(s):

Blood Transfusion ◽

Blood Donation ◽

Treatment Strategies ◽

Beneficial Effects ◽

Normovolemic Hemodilution ◽

The Mean ◽

Group 2 ◽

Perioperative Course ◽

New Treatment ◽

The Impact

Patients undergoing pancreaticoduodenectomy (PD) often require transfusion. However, transfusion-related complications and decreased blood donation in Korea encourage the development of new treatment strategies for PD patients. Although transfusion-free (TF) operation is thought to be beneficial, results supporting its beneficial effects are lacking. The aim of our study was to demonstrate the impact on PD patients of a TF program. From December 2003 to April 2013, 80 consecutive patients with periampullary lesions underwent PD performed. These patients were divided into two groups as follows: 39 PD patients in the “before TF program” (Group 1) and 41 PD patients in the “after TF program” (Group 2). Among patients in Group 2, patients who agreed with the TF program were enrolled and proceed with the TF program prospectively. Participants in the TF program had perioperative blood augmentation and intraoperative acute normovolemic hemodilution. The peri-operative data were compared with the two groups. The mean preoperative hemoglobin, operative times, and operative blood loss showed no significance between two groups. The mean postoperative hemoglobin was lower in Group 2 (11.7 g/dL vs 10.9 g/dL, P = 0.038). The mean amount of blood transfusion was significantly lower in Group 2. (950.8 mL vs 124.9 mL, P = 0.009). The TF program considerably decreases the amount of perioperative blood transfusion. The overall perioperative course and complication rate in the TF group were not inferior to those in the non-TF group. The TF program appears safe and should be considered in PD patients.

Download Full-text

Molecular alterations in triple-negative breast cancer—the road to new treatment strategies

The Lancet ◽

10.1016/s0140-6736(16)32454-0 ◽

2017 ◽

Vol 389 (10087) ◽

pp. 2430-2442 ◽

Cited By ~ 209

Author(s):

Carsten Denkert ◽

Cornelia Liedtke ◽

Andrew Tutt ◽

Gunter von Minckwitz

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Treatment Strategies ◽

The Road ◽

Molecular Alterations ◽

New Treatment

Download Full-text

Sexual dysfunction in polycystic ovary syndrome: a systematic review and meta-analysis

10.21203/rs.2.11409/v1 ◽

2019 ◽

Author(s):

Huai Heng Loh ◽

Anne Yee ◽

Huai Seng Loh ◽

Sharmilla Kanagasundram ◽

Benedict Francis ◽

...

Keyword(s):

Sexual Dysfunction ◽

Polycystic Ovary ◽

Meta Analysis ◽

Interpersonal Relationship ◽

Treatment Strategies ◽

Total Testosterone ◽

Pain Subscale ◽

Significant Difference ◽

New Treatment ◽

The Impact

Abstract Background Polycystic ovarian syndrome is a common disorder characterized by clinical or biochemical hyperandrogenism and ovulary dysfunction. Female sexual dysfunction can have adverse effects on quality of life and interpersonal relationship. Methods We conducted a meta-analysis to evaluate the prevalence and severity of sexual dysfunction in women with PCOS. Results Compared to women without PCOS, those with PCOS were younger (28.90±3.11 versus 31.42±3.37 years; p<0.0001) and had higher body mass index (27.76±3.79 versus 24.95±3.71 kg/m2; p=0.002), Ferriman-Gallwey score (9.90±3.37 versus 4.11±2.17; p<0.0001) and serum total testosterone level (2.26±0.59 versus 1.51±0.49 nmol/L; p<0.0001). There was no significant difference in mean total FSFI score (25.72±2.33 versus 26.62±3.38; p=0.608) in women with and without PCOS. For the FSFI subscales, women with PCOS had a lower score for the pain subscale than women without PCOS (4.60±0.71 versus 5.24±0.39; p<0.001). Other subscales were not significantly different between the two groups. Women with PCOS had a 1.39 higher odds (95% CI 1.13, 1.72; p=0.002, I2 11.9%) of having FSD than women without PCOS. Conclusion FSD is a prevalent and disabling condition in young women with PCOS. Sensitive probing into the intimate aspects of their sex lives is needed to further understand the struggles that afflict women with PCOS. Parallel efforts should be undertaken to investigate the impact of new treatment strategies.

Download Full-text

Effect of Stress, Depression and Type D Personality on Immune System in the Incidence of Coronary Artery Disease

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2018.217 ◽

2018 ◽

Vol 6 (8) ◽

pp. 1533-1544 ◽

Cited By ~ 5

Author(s):

Saideh Masafi ◽

Seyed Hassan Saadat ◽

Katayoun Tehranchi ◽

Roohollah Olya ◽

Mostafa Heidari ◽

...

Keyword(s):

Risk Factors ◽

Coronary Artery Disease ◽

Immune System ◽

Coronary Artery ◽

Treatment Strategies ◽

Type D Personality ◽

Type D ◽

Artery Disease ◽

New Treatment ◽

The Impact

BACKGROUND: Psychoneuroimmunology (PNI) is the study of the interaction between psychological processes and the nervous and immune systems of the human body. The impact of psychological factors on the immune system and the role of this system in Coronary Artery Disease (CAD) are confirmed. Coronary Heart Disease (CHD) is arisen due to the failure of blood and oxygen to the heart tissues.AIM: The present study aimed to describe psychoneuroimmunological processes which contribute to CAD and CHD progression.METHOD: Such psychological risk factors like stress, depression and type D personality were investigated here. Psychoneuroimmunological pathways of all three mentioned risk factors were described for CAD.RESULTS: The studies review indicated that stress could be accompanied with myocardial ischemia and help to rupture. The depression involves in the transfer of stable atherosclerotic plaque to unstable, and type D personality is effective in the initial stages of a CAD.CONCLUSION: As more information on cardiovascular immunity becomes available, this will provide a better understanding and thus act as the foundation for the potential development of new treatment strategies for treatment of cardiovascular disorders.

Download Full-text