Therapeutic Options Targeting the Ataxia-Telangiectasia Mutated (ATM)-mediated DNA Damage Response, Macropinocytosis, and Adaptive Immunity in Ovarian Cancer.

Ataxia-telangiectasia mutated (ATM) is a pivotal protein with versatile kinase activity that responds to DNA damage. While its well-established role as a DNA repair protein is widely recognized, the understanding of its noncanonical functions in ovarian cancer remains limited. Numerous studies have investigated the potential of targeting ATM for ovarian cancer treatment. In addition to its involvement in homologous recombination repair (HRR), an increasing body of research suggests that ATM plays a role in cellular metabolism and adaptive immunity. This review focuses on the current evidence and provides a perspective on how targeting ATM in ovarian cancer can address HRR-deficient genotypes, influence macropinocytosis, and enhance immune checkpoint blockade (ICB) therapy. It underscores the diverse avenues through which targeting ATM is a potential tailored treatment for ovarian cancer.

Metabolomic assessment of African snail (Achatina fulica) meal on growth performance of giant river prawn (Macrobrachium rosenbergii).

This study aimed to investigate the effects of replacing fishmeal (FM) with African giant snail (Achatina fulica) meal (SM) on the growth performance of giant river prawn (Macrobrachium rosenbergii), as well as to analyze the associated metabolomic changes. Six diets were formulated, replacing FM with SM at different inclusion levels ranging from 0 % to 100 %. Growth performance and feed conversion ratio of prawns fed diets with FM replaced by SM up to 80 % were not significantly different from control. In contrast, significantly decreased growth performance and higher feed conversion ratio (FCR) occurred with diets containing 100 % SM. To gain insights into the metabolic regulation of prawns fed different diets, a 1H NMR metabolomics approach was used to assess the metabolic changes in prawns fed diets containing 0 % and 80 % SM. The results revealed up-regulated metabolites significantly involved in several metabolic pathways, including alanine, aspartate, and glutamate metabolism; citrate cycle (TCA cycle); aminoacyl-tRNA biosynthesis; and valine, leucine, and isoleucine biosynthesis. These findings imply that including SM in the diet might modulate the regulation of muscle amino acids and tRNA synthesis, suggesting a potential impact on protein biosynthesis mechanisms. Additionally, alterations in the TCA cycle may reflect changes in carbon utilization, potentially contributing to the growth performance of giant river prawns when fishmeal is replaced with SM without adversely affecting their growth. In conclusion, this study demonstrated that SM could be a promising alternative protein source in aquafeed. The metabolomic approach provides valuable insights into the metabolic changes in prawns fed different diets, aiding in the development of more effective aquafeeds in the future. The study's limitations, such as the simplified diet formulation and the limited scope of the metabolomic analysis, were acknowledged and discussed, highlighting the need for further research to build upon these findings.

Reconstruction of the chest wall after resection of malignant peripheral nerve sheath tumor: A case report.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are a group of rare and aggressive sarcomas that often arise from major peripheral nerves and represent a notable challenge to efficacious treatment. MPNSTs can occur in any body surface and visceral organs with nerve fiber distribution. The treatment options for MPNSTs include surgery, chemotherapy, and adjuvant radiotherapy. CASE SUMMARY: A 26-year-old female cellist presented with chest pain on her left side when she squatted to lift the cello. One week later, a chest X-ray was performed and revealed fracture of the fourth rib on the left side. Three months later, the patient inadvertently touched a mass on the left side of the chest wall. Chest computed tomography (CT) three-dimensional reconstruction of the ribs revealed bone destruction of the fourth rib on the left side with a soft tissue mass shadow measuring 5.7 cm × 3.7 cm. CT-guided puncture biopsy of the tumor showed that heterotypic cells (spindle cells) tended to be nonepithelial tumor lesions. PET-CT demonstrated bone destruction and a soft tissue mass with avid 18F-fluorodeoxyglucose activity (SUVmax7.5) in the left fourth rib. The tumor of the left chest wall was resected under general anesthesia, and reconstruction of the chest wall was performed. The postoperative pathological report exhibited an MPNST. CONCLUSION: MPNSTs are relatively chemo-insensitive tumors. The mainstay of treatment for MPNSTs remains resection with tumor-free margins.

Downregulation of C-Terminal Tensin-Like Protein (CTEN) Suppresses Prostate Cell Proliferation and Contributes to Acinar Morphogenesis.

C-terminal tensin-like protein (CTEN) is a member of tensin family, which is crucial for the assembly of cell-matrix adhesome. Unlike other tensins, CTEN is selectively expressed only in a few tissues such as the prostate. However, the biological relevance of CTEN in normal prostate is poorly understood. In this study, we revealed that CTEN is selectively expressed in the prostate epithelial cells and enriched in the basal compartment. Knockdown of CTEN in RWPE-1 cells suppresses cell proliferation and results in G1/S cell cycle arrest as well as the accumulation of cyclin-dependent kinase (CDK) inhibitors, p21 and p27. Moreover, the expression of CTEN is decreased during acinar morphogenesis using Matrigel-based three-dimensional (3D) culture. In the course of acinar formation, induction of CTEN reactivates focal adhesion kinase (FAK) Y397 phosphorylation and disrupts the acini structure. This study, to our knowledge, is the first report demonstrating that downregulation of CTEN is required for luminal differentiation and acinar formation.

ΔNp63α Transcriptionally Regulates the Expression of CTEN That Is Associated with Prostate Cell Adhesion.

p63 is a member of the p53 transcription factor family and a linchpin of epithelial development and homeostasis. p63 drives the expression of many target genes involved in cell survival, adhesion, migration and cancer. In this study, we identify C-terminal tensin-like (CTEN) molecule as a downstream target of ΔNp63α, the predominant p63 isoform expressed in epithelium. CTEN belongs to the tensin family and is mainly localized to focal adhesions, which mediate many biological events such as cell adhesion, migration, proliferation and gene expression. Our study demonstrate that ΔNp63 and CTEN are both highly expressed in normal prostate epithelial cells and are down-regulated in prostate cancer. In addition, reduced expression of CTEN and ΔNp63 is correlated with prostate cancer progression from primary tumors to metastatic lesions. Silencing of ΔNp63 leads to decreased mRNA and protein levels of CTEN. ΔNp63α induces transcriptional activity of the CTEN promoter and a 140-bp fragment upstream of the transcription initiation site is the minimal promoter region required for activation. A putative binding site for p63 is located between -61 and -36 within the CTEN promoter and mutations of the critical nucleotides in this region abolish ΔNp63α-induced promoter activity. The direct interaction of ΔNp63α with the CTEN promoter was demonstrated using a chromatin immunoprecipitation (ChIP) assay. Moreover, impaired cell adhesion caused by ΔNp63α depletion is rescued by over-expression of CTEN, suggesting that CTEN is a downstream effector of ΔNp63α-mediated cell adhesion. In summary, our findings demonstrate that ΔNp63α functions as a trans-activation factor of CTEN promoter and regulates cell adhesion through modulating CTEN. Our study further contributes to the potential regulatory mechanisms of CTEN in prostate cancer progression.

Erythromycin as a Safe and Effective Treatment Option for Erythema Annulare Centrifugum.

BACKGROUND: Erythema annulare centrifugum (EAC) is an inflammatory dermatosis with unknown etiology. It is usually self-limited, but chronic disease may be difficult to treat. We observed incidentally the therapeutic effect of erythromycin for EAC among patients taking erythromycin for other diseases. AIM: To evaluate the treatment response of erythromycin for EAC. MATERIALS AND METHODS: During the study period, from July 2007 to February 2011, all patients with EAC were assigned to erythromycin stearate tablet 1000 mg per day for two weeks. EAC was diagnosed by a constellation of clinical and pathological findings. The efficacy (before and after the treatment) was assessed clinically by one dermatologist and photographically by two blinded dermatologists. Secondary outcomes included adverse drug effects and recurrence. RESULTS: Eight patients were enrolled in this study. Most patients had chronic relapsing disease with poor response to previous treatment. All the patients showed rapid response with profound reduction in the size of lesion and erythema two weeks after initiation of erythromycin treatment. The response was so obvious and complete that a coincidental response was less likely. Three patients had recurrence of disease and they tended to have more extensive lesions. Readministration of erythromycin was effective. All patients tolerated the treatment well. CONCLUSION: Our study documented erythromycin as a safe and cost-effective treatment for EAC.

Which is better to multiple rib fractures, surgical treatment or conservative treatment?

To compare the surgery and conservative treatment of multiple fractured ribs, we designed a randomized controlled trial in the single center of thoracic surgery ward. After admission condition assessment (general clinical evaluation, operation condition assessment, the digital method of pain assessment), the selected multiple fractured rib patients were told to choose surgery or conservative treatment, according to the patient will undergo surgery or conservative treatment. In the acute phase, compared with conservative treatment, patients with mechanical ventilation in time (mechanical ventilation time MV) (3.7 ± 1.4 vs. 9.5 ± 4.3), ICU stay time (8.2 ± 4.3 vs. 14.6 ± 3.2), total hospitalization days (15.3 ± 6.4 vs. 26.5 ± 6.9), the incidence of pneumonia (6.7% vs. 19.1%), mortality (1.3% vs. 5.3%) and pain score on patients (3.3 vs. 5.8) of surgical treatment group were significant lower (P < 0.05). The number of tracheostomy in surgical patients with conservative treatment (4 vs. 7) was no statistically significant difference (P > 0.05). In chronic phase, the surgical patients compared with patients with conservative treatment in the chest wall pain (2.9 ± 1.2 vs. 5.6 ± 1.7), chest wall tension (13.3% vs. 57.3%), dyspnea (5.3% vs. 22.4%) and chest wall deformity rate (4% vs. 93.5%) were lower significantly (P < 0.05). In conclusion, the surgical treatment of multiple fractured ribs could ease the acute chest pain, reduce the mechanical ventilation time and incidence of pneumonia, shorten the hospitalization days and total hospitalization days in the ICU and alleviate the forward chest wall discomfort. The speedy recovery and long-term quality of patients' life had improved significantly.

The (CCTTT) n pentanucleotide repeat polymorphism in the inducible nitric oxide synthase gene promoter and the risk of psoriasis in Taiwanese.

Recently, genome-wide association studies identified a novel psoriasis susceptibility locus tagged by two single-nucleotide polymorphisms (SNPs) rs4795067 and rs28998802, both of which are in the intronic region of inducible nitric oxide synthase (iNOS) gene. This study aimed to assess the role of (CCTTT) n pentanucleotide repeat polymorphisms in the promoter region of iNOS gene in Chinese-Taiwanese patients with psoriasis. In total, 280 patients with psoriasis and 512 control subjects were analyzed for the presence of the iNOS microsatellite polymorphism by polymerase chain reactions. The alleles were classified as S and L alleles according to the number of (CCTTT) n repeats, with the alleles with ≤13 repeats designated as S and alleles with ≥14 repeats designated as L alleles. The distribution of allele frequencies and genotypes was significantly different between the control and psoriasis groups (P = 0.040, and 0.014, respectively). After adjustment for age, sex, body mass index, smoking, diabetes, and hypertension, carriers of the LL genotype were 0.38 (95% confidence interval 0.16-0.95) times less likely than non-carriers to have psoriasis (P = 0.038). The promoter assays demonstrated that the iNOS promoter activity increases in parallel with the repeat number of (CCTTT) n in HaCaT cells. Approximately 70% of the study subjects were genotyped for rs4795067 and rs28998802. The rs4795067 is in linkage disequilibrium with the microsatellite L/S allelic classification. The association of iNOS microsatellite with psoriasis is independent of these known iNOS variants. Our results suggest that the iNOS microsatellite may contribute to the genetic background of psoriasis in Chinese-Taiwanese patients.

Genetic variants associated with phenytoin-related severe cutaneous adverse reactions.

IMPORTANCE: The antiepileptic drug phenytoin can cause cutaneous adverse reactions, ranging from maculopapular exanthema to severe cutaneous adverse reactions, which include drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions remains unknown. OBJECTIVE: To investigate the genetic factors associated with phenytoin-related severe cutaneous adverse reactions. DESIGN, SETTING, AND PARTICIPANTS: Case-control study conducted in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n=61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n=44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS), direct sequencing of the associated loci, and replication analysis were conducted using the samples from Taiwan. The initial GWAS included samples of 60 cases with phenytoin-related severe cutaneous adverse reactions and 412 population controls from Taiwan. The results were validated in (1) 30 cases with severe cutaneous adverse reactions and 130 phenytoin-tolerant controls from Taiwan, (2) 9 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and 2869 population controls from Japan, and (3) 6 cases and 374 population controls from Malaysia. MAIN OUTCOMES AND MEASURES: Specific genetic factors associated with phenytoin-related severe cutaneous adverse reactions. RESULTS: The GWAS discovered a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. Direct sequencing of CYP2C identified missense variant rs1057910 (CYP2C9*3) that showed significant association with phenytoin-related severe cutaneous adverse reactions (odds ratio, 12; 95% CI, 6.6-20; P=1.1 × 10(-17)). The statistically significant association between CYP2C9*3 and phenytoin-related severe cutaneous adverse reactions was observed in additional samples from Taiwan, Japan, and Malaysia. A meta-analysis using the data from the 3 populations showed an overall odds ratio of 11 (95% CI, 6.2-18; z=8.58; P < .00001) for CYP2C9*3 association with phenytoin-related severe cutaneous adverse reactions. Delayed clearance of plasma phenytoin was detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers, providing a functional link of the associated variants to the disease. CONCLUSIONS AND RELEVANCE: This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

Systems biology of meridians, acupoints, and chinese herbs in disease.

Meridians, acupoints, and Chinese herbs are important components of traditional Chinese medicine (TCM). They have been used for disease treatment and prevention and as alternative and complementary therapies. Systems biology integrates omics data, such as transcriptional, proteomic, and metabolomics data, in order to obtain a more global and complete picture of biological activity. To further understand the existence and functions of the three components above, we reviewed relevant research in the systems biology literature and found many recent studies that indicate the value of acupuncture and Chinese herbs. Acupuncture is useful in pain moderation and relieves various symptoms arising from acute spinal cord injury and acute ischemic stroke. Moreover, Chinese herbal extracts have been linked to wound repair, the alleviation of postmenopausal osteoporosis severity, and anti-tumor effects, among others. Different acupoints, variations in treatment duration, and herbal extracts can be used to alleviate various symptoms and conditions and to regulate biological pathways by altering gene and protein expression. Our paper demonstrates how systems biology has helped to establish a platform for investigating the efficacy of TCM in treating different diseases and improving treatment strategies.

Microsatellite polymorphism in the heme oxygenase-1 gene promoter and the risk of psoriasis in Taiwanese.

Psoriasis is a chronic disease characterized by inflammation of the skin. The expression of heme oxygenase-1 (HO-1), the rate-limiting enzyme involved in heme degradation, correlates well with the severity of psoriasis, and is a heritable trait. This study aimed to assess the role of (GT)(n) dinucleotide repeat polymorphisms in the promoter region of the HO-1 gene in Chinese-Taiwanese patients with psoriasis. In total, 288 patients with psoriasis and 542 control subjects were analyzed for the presence of the HO-1 microsatellite polymorphism by using polymerase chain reaction. The alleles were classified as the S and L alleles according to the number of (GT)(n) repeats, with the alleles with ≤26 repeats designated as S and alleles with ≥27 repeats designated as L alleles. The subjects were then classified as having S/S, S/L, or L/L genotypes according to each of their HO-1 alleles. No significant difference was observed in either the genotype or allele distribution between the patients and healthy controls. However, the average number of repeats of both alleles in psoriasis patients with late disease onset was lower than that of psoriasis patients with early disease onset (26.7 ± 3.2 vs. 27.5 ± 3.4; P = 0.043, adjusted for age and sex), but the difference was not significant after additional adjustment for body mass index, smoking, diabetes, and hypertension (P = 0.189). Our results suggest that the HO-1 microsatellite polymorphism may not contribute to the genetic background of psoriasis in Chinese-Taiwanese patients.

Lack of association between the genetic variations in the C-reactive protein gene and the risk of psoriasis among the Taiwanese.

Psoriasis is a chronic disease characterized by inflammation of the skin. The level of C-reactive protein (CRP), an inflammatory marker that correlates well with the severity of psoriasis, is a heritable trait. This study aimed to assess the role of variations in the CRP gene in patients with psoriasis among the Chinese-Taiwanese. In total, 305 patients with psoriasis and 615 control subjects were analyzed for the presence of the CRP polymorphisms rs2794521, rs3091244, and rs1800947 by polymerase chain reaction. The analysis revealed that neither polymorphism was found to be associated with psoriasis. No significant difference was observed in the genotype and allele distribution for any of the individual CRP polymorphisms between the cases and the controls. The overall haplotype frequency profiles derived from the three polymorphisms did not differ significantly between the cases and the controls. Our results suggest that these three CRP gene polymorphisms may not contribute to the genetic background of psoriasis in Chinese-Taiwanese.

Positive effect of modified Goeckerman regimen on quality of life and psychosocial distress in moderate and severe psoriasis.

Psoriasis is a chronic inflammatory skin disease with a profound effect on quality of life and psychosocial stress. The relationship between clinical improvement and psycho-social impact after treatment is complex. The objective of this study was to compare changes in quality of life and psychosocial distress, and overall cost-effectiveness, in patients with psoriasis receiving the modified Goeckerman regimen (UV irradiation and coal tar) with those receiving conventional treatment. Patients with moderate/severe psoriasis receiving the Goeckerman regimen were followed from admission to discharge. Clinical severity, was evaluated weekly using the Psoriasis Area and Severity Index (PASI). Psoriasis Disability Index (PDI) and Hospital Anxiety and Depression Scale (HADS) questionnaires were applied at admission and one month after discharge. Thirty-six patients with psoriasis receiving conventional treatment and 48 patients receiving the Goeckerman regimen were recruited to the study. The mean PASI score in the Goeckerman group decreased from 27.1 to 6.9 and PDI scores decreased from 25.3 to 13.8. HADS scores for anxiety and depression decreased significantly from 9.8 to 6.3 and 9.1 to 6.8, respectively. In comparison with conventional therapy, the modified Goeckerman regime showed similar clinical efficacy, with additional benefits in improving overall quality of life and psychosocial distress in patients with moderate/severe psoriasis, and more cost-effectiveness.

Arthroscopic shaver with refinement for axillary osmidrosis.

BACKGROUND: Minimal invasive treatment with liposuction-curettage for axillary osmidrosis has lead to clinical improvement with lower risk of complications. The incidence of skin necrosis and hematoma in the literature is very limited. Recently, arthroscopic shaver has been used for the treatment of osmidrosis with better efficacy, but associated with variable degrees of complications. OBJECTIVE: To evaluate clinical effect and complication from arthroscopic shaver with preservation of fibrovascular cords. To our knowledge this modification has not been previously described. METHOD: Thirty patients were recruited during a 1-year-period for the treatment of axillary malodor. Incision was made for the arthroscopic shaver and subcutaneous fibrovascular cords were carefully preserved. We evaluated the clinical efficacy (excellent, good, fair, and poor), complications, and subsequent recurrences. RESULTS: Among patients receiving the arthroscopic shaving for axillary osmidrosis, 93% of the patients had achieved excellent to good results, 7% with fair result and none had poor clinical efficacy. None of the patient had any skin necrosis or recurrences during clinical follow up. CONCLUSION: Arthroscopic shaving for axillary osmidrosis has been associated with variable complication rates. Our experience has indicated that preservation of fibrovascular cords protected epidermis from necrosis and such refinement will allow for more optimal clinical result and lower complications.

Facial epidermal inclusion cysts are associated with smoking in men: a hospital-based case-control study.

BACKGROUND: Epidermal inclusion cysts (EICs) are a common cutaneous disorder in adults. The etiology of EICs remains obscure. Our clinical experience suggests that smoking may be a risk factor for the development of EICs. OBJECTIVE To determine whether the number and sites of EICs are related to smoking behavior and quantity. METHODS AND MATERIALS: We retrospectively surveyed patients pathologically diagnosed with EICs at our hospital. A control group comprised patients who underwent surgical procedures for diagnoses other than EICs. Smoking history was obtained through telephone or clinical interviews. RESULTS: Three hundred one patients with EICs were identified in our archives: 217 men (mean age 37.1, range 9-77) and 84 women (mean age 41.3, range 9-82). Detailed medical records and smoking history were available for 225 patients. Two hundred twenty-five age- and sex-matched patients were enrolled in the control group. Results showed that a higher percentage of men with facial EICs than of control subjects were smokers (p<.01). No such association was found in women with EICs. CONCLUSION: Smoking may contribute to the development of EICs.

CGcgh: a tool for molecular karyotyping using DNA microarray-based comparative genomic hybridization (array-CGH).

Microarray-based comparative genomic hybridization (array-CGH) is a technique by which variations in copy numbers between two genomes can be analyzed using DNA microarrays. Array CGH has been used to survey chromosomal amplifications and deletions in fetal aneuploidies or cancer tissues. Herein we report a user-friendly, MATLAB-based, array CGH analyzing program, Chang Gung comparative genomic hybridization (CGcgh), as a standalone PC version. The analyzed chromosomal data are displayed in a graphic interface, and CGcgh allows users to launch a corresponding G-banding ideogram. The abnormal DNA copy numbers (gains and losses) can be identified automatically using a user defined window size (default value is 50 probes) and sequential student t-tests with sliding windows along with chromosomes. CGcgh has been tested in multiple karyotype-confirmed human samples, including five published cases and trisomies 13, 18, 21 and X from our laboratories, and 18 cases of which microarray data are available publicly. CGcgh can be used to detect the copy number changes in small genomic regions, which are commonly encountered by clinical geneticists. CGcgh works well for the data from cDNA microarray, spotted oligonucleotide microarrays, and Affymetrix Human Mapping Arrays (10K, 100K, 500K Array Sets). The program can be freely downloaded from http://www.mcu.edu.tw/department/biotec/en%5Fpage/CGcgh/ .

Association between P478S polymorphism of the filaggrin gene and risk of psoriasis in a Chinese population in Taiwan.

Abnormal keratinocyte terminal differentiation is one of the important characteristics of psoriatic lesions. Filaggrin (FLG) is a key protein that facilitates the terminal differentiation of the epidermis. Thus, FLG genetic variants may modify the risk of psoriasis. In total, 314 patients with psoriasis and 611 control subjects were analyzed for the presence of FLG R501X, 2282del4 mutations, and P478S (rs11584340, C/T base change) polymorphism by polymerase chain reaction (PCR). The analysis revealed that both the R501X and 2282del4 mutations were not present in a subset of 200 patients (64%) with psoriasis. In contrast, a marginally significant difference (P = 0.020) was found in the distribution of rs11584340 genotype frequencies between psoriatic patients and controls. The frequency of the TT genotype in psoriasis patients was significantly higher than in controls (37.9% vs. 29.1%, respectively, P = 0.007). The T allele frequency of patients (60.5%) was also significantly higher than that of controls (53.9%) (P = 0.007). After adjusting for age and gender, carriers of the TT genotype were 1.46 (95% CI, 1.08-1.96) times more likely than non-carriers to have psoriasis (P = 0.013). In conclusion, our results suggest that FLG P478S polymorphism may confer susceptibility to the development of psoriasis among Taiwanese Chinese.