Hypoxia-driven protease legumain promotes immunosuppression in glioblastoma.

Glioblastoma (GBM) is a hypoxic and "immune-cold" tumor containing rich stromal signaling molecules and cell populations, such as proteases and immunosuppressive tumor-associated macrophages (TAMs). Here, we seek to profile and characterize the potential proteases that may contribute to GBM immunosuppression. Legumain (LGMN) emerges as the key protease that is highly enriched in TAMs and transcriptionally upregulated by hypoxia-inducible factor 1-alpha (HIF1α). Functionally, the increased LGMN promotes TAM immunosuppressive polarization via activating the GSK-3ß-STAT3 signaling pathway. Inhibition of macrophage HIF1α and LGMN reduces TAM immunosuppressive polarization, impairs tumor progression, enhances CD8+ T cell-mediated anti-tumor immunity, and synergizes with anti-PD1 therapy in GBM mouse models. Thus, LGMN is a key molecular switch connecting two GBM hallmarks of hypoxia and immunosuppression, providing an actionable therapeutic intervention for this deadly disease.

Survival of Hydrops Fetalis with and without Fetal Intervention.

OBJECTIVES: To investigate the survival rate of hydrops fetalis after fetal interventions and neonatal intensive care. METHODS: We reviewed the medical records of patients diagnosed with hydrops fetalis from January 2009 to December 2019 at Changhua Christian Children's Hospital. All cases had abnormal fluid accumulation in at least two body compartments during pre- and postnatal examination. The primary outcome measure was the mortality rate. We also collected information regarding disease etiology, duration of hospital stay, Apgar score, gestational age at birth, initial hydrops fetalis diagnosis, fetal intervention, first albumin and pH levels, and maternal history. RESULTS: Of the 42 cases enrolled, 30 survived and 12 died; the mortality rate was 28.6%. Furthermore, 22 cases received fetal intervention, while 20 cases did not; there was no significant difference in their survival rates (75% and 68%, respectively). Survival rate was associated with gestational age at birth, initial diagnosis time, birthweight, Apgar score, initial albumin and pH levels, and gestational hypertension. Only one case was immune-mediated. Among the nonimmune-mediated cases, the three most common etiologies were lymphatic dysplasia (12/42), idiopathic disorders (10/42), and cardiovascular disorders (5/42). CONCLUSIONS: Overall, hydrops fetalis was diagnosed early, and fetal intervention was performed in a timely manner. Preterm births were more frequent, and birthweight was lower in the cases that underwent fetal intervention than in those that did not, but there was no significant between-group difference in mortality. The initial diagnosis time, gestational age at birth, birthweight, Apgar score, and first albumin and pH levels were independently associated with mortality.

Prognostic Factors for Mortality, Activity of Daily Living, and Quality of Life in Taiwanese Older Patients within 1 Year Following Hip Fracture Surgery.

BACKGROUND: Hip fractures among older adults are a major public health concern worldwide. This study investigated the potential clinical factors that predict postoperative 1-year activities of daily living (ADL), quality of life (QoL), and mortality in Taiwanese older adults following hip fracture. METHODS: This is a prospective cohort study enrolling older adults (≥60 years) who had undergone hip fracture surgery in a single medical center. The comprehensive clinical history of each patient was examined. QoL, ADL, and mortality events were recorded consecutively at 3, 6, and 12 months after operation. The multiple logistic regression model and the generalized estimating equation (GEE) were adopted to identify contributing factors for mortality and postoperative ADL and QoL prognosis, respectively. RESULTS: Among 377 participants with hip fracture, 48 died within 1 year of the index operation. ADL and QoL considerably decreased at 3 months following hip surgery. Old age, high Charlson Comorbidity Index, and American Society of Anesthesiologists grading were crucial predictors for mortality at the 1-year follow-up. The generalized estimating equation analysis indicated that the length of postoperative follow-up time, serum albumin level, patient cognitive status, and handgrip strength were considerably associated with QoL and ADL recovery prognosis in the Taiwanese older adults following hip fracture. CONCLUSIONS: Hip fractures have long-lasting effects on the older adults. Our data imply several prognosis predicting parameters that may assist clinicians in accounting for an individual's personalized risks in order to improve functional outcomes and reduce mortality.

The Clinical Feature and Treatment Outcome of Ocular Melanoma: A 34-Year Experience in a Tertiary Referral Center.

Malignant melanoma can arise from melanocytes in various structures of the eye, orbit, and ocular adnexa. We reviewed the clinical features and long-term results of all subjects with histologically proved melanoma originating from any of the ocular and periocular structures in a tertiary referral center. Overall, 88 patients including 47 men were recruited. The tumor was primarily located in the uvea, followed by the conjunctiva, orbit, eyelid, and lacrimal sac. Patients with uveal melanoma were diagnosed at a relatively younger age (47.0 years), while those with orbital and eyelid melanomas were older at presentation (79.5 years and 78.5 years, respectively). The overall local recurrence rate was 9% at a median follow-up of 41.0 months, among which orbital and eyelid melanomas recurred most commonly. The overall mortality rate was 41% in a median duration of 27.2 months (IQR, 13-58 months) from diagnosis, with the highest for lacrimal sac melanoma, followed by melanoma of the orbit, uveal, conjunctiva, and eyelid. Despite prompt local control, the risk for metastasis and mortality was high. Therefore, efficient modalities for early diagnosis and treatment of ocular melanoma are necessary.

Effects of Sarcopenic Obesity and Its Confounders on Knee Range of Motion Outcome after Total Knee Replacement in Older Adults with Knee Osteoarthritis: A Retrospective Study.

Sarcopenic obesity is closely associated with knee osteoarthritis (KOA) and has high risk of total knee replacement (TKR). In addition, poor nutrition status may lead to sarcopenia and physical frailty in KOA and is negatively associated with surgery outcome after TKR. This study investigated the effects of sarcopenic obesity and its confounding factors on recovery in range of motion (ROM) after total knee replacement (TKR) in older adults with KOA. A total of 587 older adults, aged ≥60 years, who had a diagnosis of KOA and underwent TKR, were enrolled in this retrospective cohort study. Sarcopenia and obesity were defined based on cutoff values of appendicular mass index and body mass index for Asian people. Based on the sarcopenia and obesity definitions, patients were classified into three body-composition groups before TKR: sarcopenic-obese, obese, and non-obese. All patients were asked to attend postoperative outpatient follow-up admissions. Knee flexion ROM was measured before and after surgery. A ROM cutoff of 125 degrees was used to identify poor recovery post-surgery. Kaplan-Meier curve analysis was performed to measure the probability of poor ROM recovery among study groups. Cox multivariate regression models were established to calculate the hazard ratios (HRs) of postoperative poor ROM recovery, using potential confounding factors including age, sex, comorbidity, risk of malnutrition, preoperative ROM, and outpatient follow-up duration as covariates. Analyses results showed that patients in the obese and sarcopenic-obese groups had a higher probability of poor ROM recovery compared to the non-obese group (all p < 0.001). Among all body-composition groups, the sarcopenic-obese group yielded the highest risk of postoperative physical difficulty (adjusted HR = 1.63, p = 0.03), independent to the potential confounding factors. Sarcopenic obesity is likely at the high risk of poor ROM outcome following TKR in older individuals with KOA.

Paeoniflorin elicits the anti-proliferative effects on glioma cell via targeting translocator protein 18 KDa.

As a natural compound isolated from Paeoniae radix, Paeoniflorin (PF) has been shown the antitumor effects in various types of human cancers including glioma, which is one of the serious tumors in central nervous system. Translocator protein 18 KDa (TSPO) has been shown to be relevant to the glioma aetiology. However, the regulation of PF in TSPO and neurosteriods biosynthesis on glioma is still unclear. In the present study, the glioma cell (U87 and U251) were cultured and used to quantify the bindings of PF on TSPO. Results indicated that there was not significant different between IC50 of PF and TSPO ligand PK11195. Moreover, PF exerted the anti-proliferative effects in glioma cell with a dose dependent inhibition from 12.5 to 100 µM in vitro. Consistent with the effects of PK11195, lowered levels on progesterone, allopregnanolone, as well as TSPO mRNA were induced by PF (25 and 50 µM). Furthermore, a xenograft mouse model with U87 cell-derived was significant inhibited by PF treatment, as well as the PK11195 administration. These results demonstrate that PF exerts its antitumor effects associated with the TSPO and neurosteroids biosynthesis in glioma cells could be a promising therapeutic agent for glioma therapy.

Change of Eyelid Parameters in Patients With Marin-Amat Syndrome.

PURPOSE: Marin-Amat syndrome is an acquired facial synkinesis manifesting as involuntary eyelid closure on jaw movement. The authors investigate the clinical features, especially the quantitative changes in eyelid parameters of patients with Marin-Amat syndrome. METHODS: Patients with Marin-Amat syndrome between 2015 and 2017 in a medical center were collected. Clinical features and the change of eyelid parameters, including margin reflex distance 1 (MRD-1), margin reflex distance 2 (MRD-2), and palpebral fissure height, were evaluated. RESULTS: There were 5 men and 3 women with a mean age of 76 years. All had a history of facial palsy. The mean time to onset of Marin-Amat syndrome was 4.4 years after facial palsy. Seven patients (87.5%) developed subsequent ipsilateral facial spasm after facial palsy. Most patient complaints were ptosis (62.5%) and ptosis on eating (37.5%). The mean palpebral fissure height of involved eyes decreased from 5.88 to 2 mm on jaw opening (p = 0.011), which resulted from decrease in MRD-1 (from 2.06 to 0.06 mm, p = 0.012) and MRD-2 (from 3.81 to 1.94 mm; p = 0.012). Botulinum toxin A (Botox) injection into the periorbital orbicularis muscle in 6 patients significantly relieved the change of palpebral fissure height on jaw opening compared with that before injection (9.9% vs. 68.6 %, p = 0.027). CONCLUSIONS: Most patients with Marin-Amat syndrome present with ptosis and might be overlooked or underestimated. The reduction in palpebral fissure height in our patients with Marin-Amat syndrome was due to involuntary orbicularis oculi muscle contraction, resulting in decrease of both the MRD-1 and MRD-2 on jaw opening.

Depression negatively affects patient-reported knee functional outcome after intraarticular hyaluronic acid injection among geriatric patients with knee osteoarthritis.

PURPOSE: Intraarticular hyaluronic acid injection (IAHA) is a popular treatment for knee osteoarthritis (OA). This study investigates whether depression, anxiety, and pain affect self-reported knee function in geriatric OA people who have received IAHA. METHODS: Through convenience sampling, 102 geriatric patients (mean age = 70.91 ± 7.19; 28 males) with knee OA who had undergone IAHA participated in this study. All participants self-reported depression using the Geriatric Depression Scale (GDS), anxiety using the State-Trait Anxiety Inventory (STAI), knee function using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and the International Knee Documentation Committee subjective knee evaluation form (IKDC), and pain severity using the Visual Analogue Scale (VAS). They completed the aforementioned questionnaires at baseline before injection and then again at 2-, 4-, and 6-month follow-ups. RESULTS: Depression was significantly associated with IKDC, WOMAC physical function subscale, and total WOMAC scores. Anxiety was only significantly associated with the WOMAC pain subscale score. Pain severity was significantly associated with IKDC, WOMAC stiffness subscale, WOMAC physical function subscale, and total WOMAC scores. CONCLUSION: Given that depression negatively affected patient-reported knee function among geriatric OA patients who had undergone IAHA, further attention should be paid to the depressive status of this population.

Conjunctival papilloma: Clinical features, outcome, and factors related to recurrence.

PURPOSE: The purpose of the study was to evaluate the clinical features, treatment, and outcome of patients with conjunctival papilloma. MATERIALS AND METHODS: Twenty-two patients (22 eyes) with biopsy-proven conjunctival papilloma between January 2005 and January 2015 in a tertiary medical center were retrospectively reviewed. Clinical profiles, treatment, outcome, and factors related to recurrence were evaluated. RESULTS: There were 16 males (73%) and 6 females (27%), with a mean age of 47 years. The most common location of conjunctival papilloma was the caruncle (43%), followed by palpebral conjunctiva (29%), bulbar conjunctiva (14%), and fornix (14%). Recurrence developed in five patients (22.7%). The risk of postoperative recurrence was significantly related to the presence of bulbar conjunctival papilloma with corneal involvement (P = 0.043) and surgical excision alone (P = 0.039). One case with multiple recurrences developed nonkeratinizing carcinoma. Two young females developed conjunctival papilloma even after receiving human papillomavirus vaccinations. CONCLUSION: The recurrence of conjunctival papilloma is not uncommon, especially for those patients underwent surgical excision alone. Surgical excision with adjunctive therapy and long-term follow-up is rational for the treatment of conjunctival papilloma.

Comparison of the Clinical Characteristics and Outcome of Benign and Malignant Eyelid Tumors: An Analysis of 4521 Eyelid Tumors in a Tertiary Medical Center.

We retrospectively reviewed the clinical features and outcome of benign and malignant eyelid tumors from 1995 to 2015 in a tertiary medical center. Among 4,521 histologically confirmed eyelid tumors, 4,294 (95.0%) were benign tumors and 227 (5.0%) were malignant tumors. The mean age at diagnosis was significantly higher in patients with malignant lid tumors than those with benign lid tumors (72.5 and 55.4 years, resp., p < 0.001). The most common benign eyelid tumors were intradermal nevus (21.1%), followed by seborrheic keratosis (12.6%) and xanthelasma (11.2%). The most common malignant eyelid tumors were basal cell carcinomas (57.8%), followed by sebaceous gland carcinomas (21.1%) and squamous cell carcinomas (10.1%). There was a relative male predominance (63.4% and 49.2%, resp., p < 0.001) and higher recurrence rate (11.9% and 4.4%, resp., p < 0.001) in malignant lid tumors as compared with those of benign lid tumors. Twenty-two patients (9.7%) received orbital exenteration/enucleation. Eight patients (3.5%) with malignant lid tumors died of disease. Patients with eyelid melanoma were associated with a high mortality rate (25.0%). It is important to differentiate between benign and malignant eyelid tumors, because they may cause cosmetic disfigurement and severe morbidity, especially in those with malignant eyelid tumors.

Relationship between CCR2-V64I polymorphism and cancer risk: a meta-analysis.

BACKGROUND AND OBJECTIVES: The role of CCR2-V64I polymorphism in various cancers has been reported in many studies. However, results from published studies on the association between CCR2-V64I polymorphism and cancer risk are conflicting. Therefore, we performed a meta-analysis to estimate the overall cancer risk associated with the polymorphism. METHODS: Electronic searches of PubMed and EMBASE were conducted for all publications on the association between this variant and cancer. Odds ratios (OR) with 95% confidence intervals (95% CI) were used to access the strength of this association. RESULTS: Sixteen studies with 2661 cancer patients and 5801 healthy controls were included. Overall, significant association was found between the CCR2-V64I polymorphism and cancer risk (OR=1.84, 95% CI=1.35-2.51, AA vs GA/GG, P=0.37). In the subgroup analysis stratified by cancer types, there was a significant association between this polymorphism and bladder cancer (OR=2.06, 95% CI=1.02-4.15, AA vs GA/GG, P=0.11), cervical cancer (OR=3.34, 95% CI=1.48-7.50, AA vs GG, P=0.56), and oral cancer (OR=2.04, 95% CI=1.46-2.84, GA vs GG, P=0.70). In the subgroup analysis stratified by ethnicities, an increased cancer risk was also found in Europeans (OR=2.31, 95% CI=1.45-3.68, AA vs GA/GG, P=0.16) and Asians (OR=1.88, 95% CI=1.12-3.16, AA vs GA/GG, P=0.92). CONCLUSION: This meta-analysis suggested that CCR2-V64I polymorphism may contribute to an increased risk of cancer.

Effects of balance training on functional outcome after total knee replacement in patients with knee osteoarthritis: a randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness of additional balance training on mobility and function outcome in patients with knee osteoarthritis after total knee replacement. DESIGN: A prospective intervention study and randomized controlled trial. SETTING: A university-based teaching hospital. PARTICIPANTS: Patients who received total knee replacement surgery were recruited sequentially from the orthopedic department. They were randomly assigned to either the experimental group or control group. INTERVENTIONS: The control group received conventional function training for eight weeks. The experimental group not only received the same conventional training as the control group, but also received additional balance exercises in each admission. MAIN OUTCOME MEASURES: Before and after training we took the following measurements: distance of functional forward reach; duration of single leg stance; timed sit-to-stand test; timed up-and-down stair test; timed 10-m walk; timed up-and-go test; and the Western Ontario and McMaster Universities Osteoarthritis Index score. RESULTS: 58 patients in the experimental group with a mean (SD) age of 71.4 (6.6) years and 55 in the control group with mean (SD) age of 72.9 (7.3) years, completed the study. After eight-weeks intervention with additional balance exercises, the experimental group demonstrated significant changes in 10-m walk (P < 0.001, 95% confidence interval (CI): 3.6 to 4.4 seconds) and in timed up-and-go (P < 0.001, 95% confidence interval: 2.6 to 3.4 seconds) tests. Significant changes of all other measures and Western Ontario and McMaster Universities Osteoarthritis Index score were also observed in the experimental group (all P < 0.001). CONCLUSION: Additional balance training exerted a significant beneficial effect on the function recovery and mobility outcome in patients with knee osteoarthritis after total knee replacement.

[Real-time PCR used to detect p53 gene damage in workers exposed to arsenic].

OBJECTIVE: To evaluate the relationship between the metabolism of arsenic and the damage of exon 5 and 8 of p53 gene from workers in a arsenic mill, and with real-time PCR technique, to establish the method probing the gene-specific DNA damage in people. METHODS: By real-time PCR, the damages of exon 5 and 8 of p53 gene were probed in 37 workers exposed highly to, 16 manager and logistic employees exposed less to an arsenic mill in Yunnan province, and also 25 local people who did not contact with any white arsenic in near past time. At the same time, the urinary total and organic arsenic of workers were detected. The correlation between metabolism of arsenic and damage of p53 gene was evaluated. RESULTS: Total urinary arsenic concentrations were (1.18 +/- 0.76) mg/L and (0.32 +/- 0.28) mg/L for high and low exposed male workers, and 0.23 mg/L, (0.53 +/- 0. 30) mg/L for high and low exposed females. Organic urinary arsenic concentrations were (0.48 +/- 0.37) mg/L and (0.08 +/- 0.05) mg/L for high and low exposed males, and 0.11 mg/L, (0.30 +/- 0.24) mg/L for high and low exposed females. The total and organic urinary arsenic of high exposed group was higher than that of control male (P < 0.05), all in control group were lower than 0.02 mg/L for reference. The Ct relative value of exon 5 of p53 gene in high exposed group was higher than that in control male (P < 0.05), and the increased tendency of Ct relative value of exon 5 of p53 gene was found in workers with organic arsenic concentration going up (r(s) = 0.355, P = 0.011). The Ct relative value of exon 8 of p53 gene in low exposed group was higher than that in control male (P < 0.05), but the difference between high exposed and low exposed or reference's was not obvious (P > 0.05). CONCLUSION: The damages in exon 5 and 8 of p53 gene in workers exposed to arsenic may be induced. The metabolism of arsenic may be very important in the damage of exon 5. It is feasible for real-time PCR technique used to detect gene-specific DNA damage in people.