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BioRxiv : the Preprint Server For... Jun 2024Acral melanoma (AM) is an aggressive melanoma variant that arises from palmar, plantar, and nail unit melanocytes. Compared to non-acral cutaneous melanoma (CM), AM is...
Acral melanoma (AM) is an aggressive melanoma variant that arises from palmar, plantar, and nail unit melanocytes. Compared to non-acral cutaneous melanoma (CM), AM is biologically distinct, has an equal incidence across genetic ancestries, typically presents in advanced stage disease, is less responsive to therapy, and has an overall worse prognosis. Independent analysis of published genomic and transcriptomic sequencing identified that receptor tyrosine kinase (RTK) ligands and adapter proteins are frequently amplified, translocated, and/or overexpressed in AM. To target these unique genetic changes, a zebrafish acral melanoma model was exposed to a panel of narrow and broad spectrum multi-RTK inhibitors, revealing that dual FGFR/VEGFR inhibitors decrease acral-analogous melanocyte proliferation and migration. The potent pan-FGFR/VEGFR inhibitor, Lenvatinib, uniformly induces tumor regression in AM patient-derived xenograft (PDX) tumors but only slows tumor growth in CM models. Unlike other multi-RTK inhibitors, Lenvatinib is not directly cytotoxic to dissociated AM PDX tumor cells and instead disrupts tumor architecture and vascular networks. Considering the great difficulty in establishing AM cell culture lines, these findings suggest that AM may be more sensitive to microenvironment perturbations than CM. In conclusion, dual FGFR/VEGFR inhibition may be a viable therapeutic strategy that targets the unique biology of AM.
PubMed: 38948879
DOI: 10.1101/2024.06.15.599116 -
BioRxiv : the Preprint Server For... Jun 2024DNA replication is regulated by factors that promote or inhibit initiation. In YabA is a negative regulator of DNA replication initiation while the newly identified...
UNLABELLED
DNA replication is regulated by factors that promote or inhibit initiation. In YabA is a negative regulator of DNA replication initiation while the newly identified kinase CcrZ is a positive regulator. The consequences of under-initiation or over-initiation of DNA replication to genome stability remain unclear. In this work, we measure origin to terminus ratios as a proxy for replication initiation activity. We show that Δ and several alleles under-initiate DNA replication while ablation of or overproduction of CcrZ leads to over-initiation. We find that cells under-initiating DNA replication have few incidents of replication fork stress as determined by low formation of RecA-GFP foci compared with wild type. In contrast, cells over-initiating DNA replication show levels of RecA-GFP foci formation analogous to cells directly challenged with DNA damaging agents. We show that cells under-initiating and over-initiating DNA replication were both sensitive to mitomycin C and that changes in replication initiation frequency cause increased sensitivity to genotoxic stress. With these results, we propose that cells under-initiating DNA replication are sensitive to DNA damage due to a shortage of DNA for repair through homologous recombination. For cells over-initiating DNA replication, we propose that an increase in the number of replication forks leads to replication fork stress which is further exacerbated by chromosomal DNA damage. Together, our study shows that DNA replication initiation frequency must be tightly controlled as changes in initiation influence replication fork fate and the capacity of cells to efficiently repair damage to their genetic material.
IMPORTANCE
The regulation of DNA replication is fundamental to cell growth and cell cycle control. In eukaryotes under-initiation or over-initiation leads to genome instability. For bacteria, it is unclear how changes in replication initiation frequency impact DNA replication status and genome integrity. We show that tight regulation of DNA replication initiation is critical for maintaining genome integrity. Cells over-initiating or under-initiating DNA replication are sensitive to DNA damage. Further, cells over-initiating DNA replication experience replication fork stress at levels that phenocopy cells encountering DNA damage from the crosslinking agent mitomycin C. Our results establish the critical importance of properly regulating DNA replication initiation frequency because an imbalance in initiation results in replication fork perturbations, deficiencies in DNA repair, and genome instability.
PubMed: 38948856
DOI: 10.1101/2024.06.18.599555 -
BioRxiv : the Preprint Server For... Jun 2024Mitochondrial creatine kinases are key players in maintaining energy homeostasis in cells by working in conjunction with cytosolic creatine kinases for energy transport...
Mitochondrial creatine kinases are key players in maintaining energy homeostasis in cells by working in conjunction with cytosolic creatine kinases for energy transport from mitochondria to cytoplasm. High levels of MtCK observed in Her2+ breast cancer and inhibition of breast cancer cell growth by substrate analog, cyclocreatine, indicate dependence of cancer cells on the 'energy shuttle' for cell growth and survival. Hence, understanding the key mechanistic features of creatine kinases and their inhibition plays an important role in the development of cancer therapeutics. Herein, we present the mutational and structural investigation on understudied ubiquitous mitochondrial creatine kinase (uMtCK). Our cryo-EM structures and biochemical data on uMtCK showed closure of the loop comprising residue His61 is specific to and relies on creatine binding and the reaction mechanism of phosphoryl transfer depends on electrostatics in the active site. In addition, the previously identified covalent inhibitor CKi showed inhibition in breast cancer BT474 cells, however our biochemical and structural data indicated that CKi is not a potent inhibitor for breast cancer due to strong dependency on the covalent link formation and inability to induce conformational changes upon binding.
PubMed: 38948784
DOI: 10.1101/2024.06.18.598884 -
Turkish Journal of Physical Medicine... Jun 2024This study aimed to compare the effectiveness of local ozone (O) injection versus corticosteroid injection in the treatment of mild to moderate carpal tunnel syndrome...
OBJECTIVES
This study aimed to compare the effectiveness of local ozone (O) injection versus corticosteroid injection in the treatment of mild to moderate carpal tunnel syndrome (CTS).
PATIENTS AND METHODS
This double-blind randomized controlled trial was performed on 42 patients (9 males, 33 females; mean age: 46.7±2.1 years; range, 18 to 70 years) with mild to moderate CTS between May 2021 and June 2021. The corticosteroid group (n=21) was injected with 40 mg triamcinolone, and in the O group B (n=21), 4 mL of a 10 mcg/mL oxygen (O)-O mixture was injected. Symptom severity and functional impairments were assessed using a Visual Analog Scale and Boston Carpal Tunnel Questionnaire. Electrodiagnostic and ultrasonographic parameters were obtained at baseline and eight weeks after the procedure.
RESULTS
The O-O solution improved pain and Boston Carpal Tunnel Questionnaire score after eight weeks (p<0.001); however, the change was nonsignificant compared to the corticosteroid group (p>0.05). Sensory nerve and compound muscle action potential latencies were not significantly changed eight weeks after O-O injection (p>0.05), while both were significantly decreased in the steroid injection group (p<0.001). Volar bulging and median nerve cross-section surface area were not improved after O-O injection, while the improvement was significant in the corticosteroid arm (p=0.02).
CONCLUSION
Symptoms in patients with mild to moderate CTS may be alleviated by local O-O injection; however, electrodiagnostic and ultrasonographic indices may be unchanged. Corticosteroid local injection may alleviate patient symptoms along with electrodiagnostic and ultrasonographic parameters.
PubMed: 38948651
DOI: 10.5606/tftrd.2024.12590 -
Turkish Journal of Physical Medicine... Jun 2024This study aimed to evaluate the effects of the combined hydrolyzed type 2 collagen, methylsulfonylmethane (MSM), glucosamine sulfate (GS), and chondroitin sulfate (CS)...
OBJECTIVES
This study aimed to evaluate the effects of the combined hydrolyzed type 2 collagen, methylsulfonylmethane (MSM), glucosamine sulfate (GS), and chondroitin sulfate (CS) supplement on knee pain intensity in patients with knee osteoarthritis (OA).
PATIENTS AND METHODS
This multicenter, observational, noninterventional study included 98 patients (78 females, 20 males; mean age: 52.8±6.5 years; range, 40 to 64 years) who had Grade 1-3 knee OA between May 2022 and November 2022. The patients were prescribed the combination of hydrolyzed type 2 collagen, MSM, GS, and CS as a supplement for knee OA. The sachet form of the combined supplement containing 1250 mg hydrolyzed type 2 collagen, 750 mg MSM, 750 mg GS, and 400 mg CS was used once daily for two consecutive months. Patients were evaluated according to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Visual Analog Scale (VAS)-pain, and Health Assessment Questionnaire (HAQ). Patients were scheduled to visit for follow-up four weeks (Visit 2) and eight weeks (Visit 3) after Visit 1 (baseline; day 0 of the study).
RESULTS
For the VAS-pain, WOMAC, WOMAC-subscale, and HAQ scores, the differences in improvement between the three visits were significant (p<0.001 for all). The patient compliance with the supplement was a median of 96.77%, both for Visit 2 and Visit 3.
CONCLUSION
The combination of hydrolyzed type 2 collagen, MSM, GS, and CS for eight weeks in knee OA was considered an effective and safe nutritional supplement.
PubMed: 38948650
DOI: 10.5606/tftrd.2024.13735 -
Turkish Journal of Physical Medicine... Jun 2024This study aims to compare the efficacy of intra-articular platelet-rich plasma (PRP) injections over a saline placebo in terms of reduction of pain and impact on...
OBJECTIVES
This study aims to compare the efficacy of intra-articular platelet-rich plasma (PRP) injections over a saline placebo in terms of reduction of pain and impact on quality of life among patients with hip osteoarthritis.
PATIENTS AND METHODS
A total of 60 patients (29 males, 31 females, mean age: 57.9±7.3 years; range, 47 to 69 years) with known hip osteoarthritis of Kellgren-Lawrance (KL) Grades 2/3 were randomized into placebo (n=30) and PRP groups (n=30) between June 2014 and June 2015. Both groups received intra-articular injections into the hip joint under ultrasound guidance for three consecutive weeks. The patients were followed for six months, and pain reduction was assessed using the Visual Analog Scale (VAS), Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire, and Short Form Health Survey-36 (SF-36).
RESULTS
Intra-articular PRP treatment showed no advantage over a saline placebo in terms of VAS scores during activity. Both groups showed a significant improvement in VAS activity scores at one and six months. The placebo group showed improvements in VAS resting scores, whereas the PRP group did not. Both groups showed no improvement in WOMAC-total scores. Both groups showed no significant improvement across most SF-36 domains with the exception of improved physical role functioning at one month and general health at one and six months in the placebo group.
CONCLUSION
Intra-articular injections of PRP show no significant difference compared to a saline placebo over a period of six months on pain, function, and quality of life scores in patients with hip osteoarthritis.
PubMed: 38948640
DOI: 10.5606/tftrd.2024.13855 -
Turkish Journal of Physical Medicine... Jun 2024This study aimed to objectively and quantitatively exhibit morning stiffness by using electrophysiological methods.
OBJECTIVES
This study aimed to objectively and quantitatively exhibit morning stiffness by using electrophysiological methods.
PATIENTS AND METHODS
The prospective, controlled study was conducted with 52 participants between February 2013 and February 2014. Of the participants, 26 were recruited among RA patients (3 males, 23 females; mean age: 55.9±11.2 years; range, 24 to 74 years) followed at the rheumatology clinic, and 26 were healthy subjects (4 males, 22 females; mean age: 54.9±8.3 years; range, 41 to 70 years) for the control group. Duration and severity of morning stiffness were recorded for all participants. Activity of disease and functional status were evaluated by the Disease Activity Score 28 and Health Assessment Questionnaire (HAQ), respectively. Electrophysiological reaction times, severity of pain (Visual Analog Scale), HAQ, and grip strength were measured for each participant twice in 24 h in the morning (08:00-09:00 am) and afternoon (03:00-05:00 pm).
RESULTS
In the RA group, motor reaction and response times and severity of pain values were significantly lower in the afternoon compared to the morning (p=0.030, p=0.031, and p=0.002, respectively), and hand grip strengths were significantly higher in the afternoon (p=0.007). In the control group, no change was observed between morning and afternoon measurements in the strength and reaction time variables.
CONCLUSION
Our hypothesis that stiffness would slow down the movements in the morning in RA was supported by the prolonged motor and response times in the morning compared to the afternoon. However, in the control group (no morning stiffness), there was no difference in reaction time variables between the morning and afternoon, objectively demonstrating the concept of morning stiffness in this study.
PubMed: 38948637
DOI: 10.5606/tftrd.2024.12219 -
Journal of Family Medicine and Primary... May 2024Osteoarthritis (OA) is a noninflammatory joint disease. If OA of the knee causes pain, decreased muscle strength and joint stiffness, exercise therapy is one of the most...
INTRODUCTION AND AIM
Osteoarthritis (OA) is a noninflammatory joint disease. If OA of the knee causes pain, decreased muscle strength and joint stiffness, exercise therapy is one of the most effective treatments for the disease. The aim of the present study was to evaluate the effect of aquatherapy on pain intensity and performance in women with OA with the assumption that it causes weightlessness.
METHODS
This is a quasiexperimental study. The sample size included 60 people who were randomly divided into experimental and control groups. The visual analogue scale was used to assess pain and timed up and go test (TUG), 30 Second Sit to Stand Test (30-S-CS), and 40-meter fast-paced walk test (40 MW) were used to assess performance. Data analysis was carried out using SPSS ver. 22.
RESULTS
The results of the present study showed a decrease in pain intensity from moderate to mild intensity. Also, physical performance dimensions in patients with OA were improved, so that the average TUG increased from 14.06 to 8.8 s. The average S-CS frequency increased from 4.86 to 8.4 s and 90 MW decreased from the average 93.43 to 72.66 s.
DISCUSSION AND CONCLUSION
Lower limb muscle strength, and physical performance can be improved and pain intensity can be reduced in patients with OA by performing aquatherapy three times a week for 8 weeks.
PubMed: 38948627
DOI: 10.4103/jfmpc.jfmpc_1088_23 -
World Journal of Hepatology Jun 2024Achievement of a 'clinical cure' in chronic hepatitis B (CHB) implies sustained virological suppression and immunological control over the infection, which is the ideal... (Review)
Review
Achievement of a 'clinical cure' in chronic hepatitis B (CHB) implies sustained virological suppression and immunological control over the infection, which is the ideal treatment goal according to domestic and international CHB management guidelines. Clinical practice has shown encouraging results for specific patient cohorts using tailored treatment regimens. These regimens incorporate either nucleos(t)ide analogs, immunomodulatory agents such as pegylated interferon α, or a strategic combination of both, sequentially or concurrently administered. Despite these advancements in the clinical handling of hepatitis B, achieving a clinical cure remains elusive for a considerable subset of patients due to the number of challenges that preclude the realization of optimal treatment outcomes. These include, but are not limited to, the emergence of antiviral resistance, incomplete immune recovery, and the persistence of covalently closed circular DNA. Moreover, the variance in response to interferon therapy and the lack of definitive biomarkers for treatment cessation also contribute to the complexity of achieving a clinical cure. This article briefly overviews the current research progress and existing issues in pursuing a clinical cure for hepatitis B.
PubMed: 38948438
DOI: 10.4254/wjh.v16.i6.900 -
World Journal of Experimental Medicine Jun 2024Eribulin is a non-taxane synthetic analogue approved in many countries as third-line treatment for the treatment of patients with metastatic breast cancer. In addition... (Review)
Review
Eribulin is a non-taxane synthetic analogue approved in many countries as third-line treatment for the treatment of patients with metastatic breast cancer. In addition to its mitotic property, eribulin has non-mitotic properties including but not limited to, its ability to induce phenotypic reversal of epithelial to mesenchymal transition, vascular remodelling, reduction in immunosuppressive tumour microenvironment. Since approval, there has been a surge in studies investigating the application of eribulin as an earlier-line treatment and also in combination with other agents such as immunotherapy and targeted therapy across all breast cancer sub-types, including hormone receptor positive, HER2 positive and triple negative breast cancer, many demonstrating promising activity. This review will focus on the application of eribulin in the treatment of metastatic breast cancer across all subtypes including its role as an earlier-line agent, its toxicity profile, and potential future directions.
PubMed: 38948420
DOI: 10.5493/wjem.v14.i2.92558