-
Cells Nov 2023This review on acne transcriptomics allows for deeper insights into the pathogenesis of acne and isotretinoin's mode of action. Puberty-induced insulin-like growth... (Review)
Review
This review on acne transcriptomics allows for deeper insights into the pathogenesis of acne and isotretinoin's mode of action. Puberty-induced insulin-like growth factor 1 (IGF-1), insulin and androgen signaling activate the kinase AKT and mechanistic target of rapamycin complex 1 (mTORC1). A Western diet (hyperglycemic carbohydrates and milk/dairy products) also co-stimulates AKT/mTORC1 signaling. The AKT-mediated phosphorylation of nuclear FoxO1 and FoxO3 results in their extrusion into the cytoplasm, a critical switch which enhances the transactivation of lipogenic and proinflammatory transcription factors, including androgen receptor (AR), sterol regulatory element-binding transcription factor 1 (SREBF1), peroxisome proliferator-activated receptor γ (PPARγ) and signal transducer and activator of transcription 3 (STAT3), but reduces the FoxO1-dependent expression of GATA binding protein 6 (GATA6), the key transcription factor for infundibular keratinocyte homeostasis. The AKT-mediated phosphorylation of the p53-binding protein MDM2 promotes the degradation of p53. In contrast, isotretinoin enhances the expression of p53, FoxO1 and FoxO3 in the sebaceous glands of acne patients. The overexpression of these proapoptotic transcription factors explains isotretinoin's desirable sebum-suppressive effect via the induction of sebocyte apoptosis and the depletion of BLIMP1(+) sebocyte progenitor cells; it also explains its adverse effects, including teratogenicity (neural crest cell apoptosis), a reduced ovarian reserve (granulosa cell apoptosis), the risk of depression (the apoptosis of hypothalamic neurons), VLDL hyperlipidemia, intracranial hypertension and dry skin.
Topics: Humans; Isotretinoin; Proto-Oncogene Proteins c-akt; Tumor Suppressor Protein p53; Transcriptome; Acne Vulgaris; Mechanistic Target of Rapamycin Complex 1; Transcription Factors
PubMed: 37998335
DOI: 10.3390/cells12222600 -
Cureus Sep 2023Hypothyroidism means an underactive thyroid gland. This leads to a decrease in the functioning of the thyroid gland. It is a very common endocrine disorder that causes... (Review)
Review
Hypothyroidism means an underactive thyroid gland. This leads to a decrease in the functioning of the thyroid gland. It is a very common endocrine disorder that causes under-secretion of thyroid hormones, mainly thyroxine (T4) and triiodothyronine (T3). It affects people of every age group but is more commonly found in women and older people. The symptoms of hypothyroidism can go unnoticed, may not be specific, and may overlap with other conditions, which makes it harder to diagnose it in some cases. Common symptoms include fatigue, weight gain, increased sensitivity to cold (cold intolerance), irregular bowel movements (constipation), and dry skin (xeroderma). These conditions are mostly the result of a low metabolic rate in the body. Weight gain occurs due to a decrease in fat-burning rate and cold intolerance due to a decrease in heat production by the body. This condition can be caused by a variety of factors, including autoimmune diseases, radiation therapy, thyroid gland removal surgeries, and certain medications. The diagnosis of hypothyroidism is based on laboratory tests that measure the levels of thyroid hormones (T3 and T4) in the blood. Treatment typically involves lifelong hormone replacement therapy with synthetic thyroid hormone replacement medication, such as levothyroxine, to help regulate hormone levels in the body. People with hypothyroidism may need to have their medication dosage adjusted over time. If hypothyroidism is left untreated, it can lead to severe complications like mental retardation, delayed milestones, etc., in infants and heart failure, infertility, myxedema coma, etc., in adults. With appropriate treatment, the symptoms of hypothyroidism can be effectively managed, and most people with the condition can lead normal, healthy lives. Lifestyle modifications like eating healthy food and exercising regularly can help manage the symptoms and improve the quality of life.
PubMed: 37908940
DOI: 10.7759/cureus.46241 -
The International Journal of Lower... Sep 2023Feet suffer significant stress throughout a lifetime and undergo ageing-associated problems due to gradual tissue degeneration affecting the skin, connective tissue, and... (Review)
Review
Feet suffer significant stress throughout a lifetime and undergo ageing-associated problems due to gradual tissue degeneration affecting the skin, connective tissue, and nerves. Oxygen supply to the tissues may be diminished. The skin gets dry and calluses, ulcers and fungal infections of the skin and nails are not uncommon. Ligaments and tendons degenerate and, without proper prevention, deformities including claw toes, hammer toes, tendonitis, and bursitis may occur. Skeletal toe deformities such as bunions, bony spurs, and hallux valgus may increase discomfort, while stress fractures may have an adverse impact on the patients' quality of life. The ageing foot pathology may add up to common age-related problems, such as crystal deposition arthropathies, diabetes mellitus, peripheral circulatory disorders, and peripheral edema, increasing morbidity. This review summarizes ageing-related feet problems, focusing on prevention and treatment. Foot health has a paramount role in overall wellbeing, therefore prevention, proper foot care, and prompt diagnosis and management of ageing-related changes are vital for maintaining a healthy, active status.
PubMed: 37750199
DOI: 10.1177/15347346231203279 -
Journal of Clinical Oncology : Official... Nov 2023V600 mutation is detected in 5%-10% of pediatric high-grade gliomas (pHGGs), and effective treatments are limited. In previous trials, dabrafenib as monotherapy or in...
PURPOSE
V600 mutation is detected in 5%-10% of pediatric high-grade gliomas (pHGGs), and effective treatments are limited. In previous trials, dabrafenib as monotherapy or in combination with trametinib demonstrated activity in children and adults with relapsed/refractory V600-mutant HGG.
METHODS
This phase II study evaluated dabrafenib plus trametinib in patients with relapsed/refractory V600-mutant pHGG. The primary objective was overall response rate (ORR) by independent review by Response Assessment in Neuro-Oncology criteria. Secondary objectives included ORR by investigator determination, duration of response (DOR), progression-free survival, overall survival (OS), and safety.
RESULTS
A total of 41 pediatric patients with previously treated V600-mutant HGG were enrolled. At primary analysis, median follow-up was 25.1 months, and 51% of patients remained on treatment. Sixteen of 20 discontinuations were due to progressive disease in this relapsed/refractory pHGG population. Independently assessed ORR was 56% (95% CI, 40 to 72). Median DOR was 22.2 months (95% CI, 7.6 months to not reached [NR]). Fourteen deaths were reported. Median OS was 32.8 months (95% CI, 19.2 months to NR). The most common all-cause adverse events (AEs) were pyrexia (51%), headache (34%), and dry skin (32%). Two patients (5%) had AEs (both rash) leading to discontinuation.
CONCLUSION
In relapsed/refractory V600-mutant pHGG, dabrafenib plus trametinib improved ORR versus previous trials of chemotherapy in molecularly unselected patients with pHGG and was associated with durable responses and encouraging survival. These findings suggest that dabrafenib plus trametinib is a promising targeted therapy option for children and adolescents with relapsed/refractory V600-mutant HGG.
Topics: Adult; Adolescent; Humans; Child; Melanoma; Proto-Oncogene Proteins B-raf; Oximes; Pyridones; Pyrimidinones; Glioma; Antineoplastic Combined Chemotherapy Protocols; Mutation
PubMed: 37643378
DOI: 10.1200/JCO.23.00558 -
Blood Advances Aug 2023Langerhans cell histiocytosis (LCH) is a rare, heterogenous, neoplastic disorder primarily affecting children. BRAF mutations have been reported in >50% of patients with...
Langerhans cell histiocytosis (LCH) is a rare, heterogenous, neoplastic disorder primarily affecting children. BRAF mutations have been reported in >50% of patients with LCH. The selective BRAF inhibitor, dabrafenib, in combination with the MEK1/2 inhibitor, trametinib, has been approved in select BRAF V600-mutant solid tumors. Two open-label phase 1/2 studies were conducted in pediatric patients with BRAF V600-mutant, recurrent/refractory malignancies treated with dabrafenib monotherapy (CDRB436A2102; NCT01677741) or dabrafenib plus trametinib (CTMT212X2101; NCT02124772). The primary objectives of both studies were to determine safe and tolerable doses that achieve similar exposure to the approved doses for adults. Secondary objectives included safety, tolerability, and preliminary antitumor activity. Thirteen and 12 patients with BRAF V600-mutant LCH received dabrafenib monotherapy and in combination with trametinib, respectively. Investigator-assessed objective response rates per Histiocyte Society criteria were 76.9% (95% confidence interval [CI], 46.2-95.0) and 58.3% (95% CI, 27.7-84.8) in the monotherapy and combination studies, respectively. More than 90% of responses were ongoing at study completion. The most common treatment-related adverse events (AEs) were vomiting and increased blood creatinine with monotherapy and pyrexia, diarrhea, dry skin, decreased neutrophil count, and vomiting with combination therapy. Two patients each discontinued treatment with monotherapy and combination therapy because of AEs. Overall, dabrafenib monotherapy or in combination with trametinib demonstrated clinical efficacy and manageable toxicity in relapsed/refractory BRAF V600-mutant pediatric LCH, with most responses ongoing. Safety was consistent with that reported in other pediatric and adult conditions treated with dabrafenib plus trametinib.
Topics: Adult; Child; Humans; Proto-Oncogene Proteins B-raf; Histiocytosis, Langerhans-Cell
PubMed: 36884302
DOI: 10.1182/bloodadvances.2022008414