Risk factors associated with the survival of endodontically treated teeth: A retrospective chart review.

BACKGROUND: Studies on risk factors affecting tooth retention after endodontic treatment in dental school settings are limited. Understanding these factors is crucial for preserving teeth. The aim of this retrospective study was to evaluate patient- and tooth-level risk factors associated with the survival of endodontically treated teeth. METHODS: Electronic health records of patients who underwent endodontic treatment at the School of Dental Medicine at the University of Pennsylvania from 2017 through 2020 were analyzed. Patient-level factors included age, sex, American Society of Anesthesiologists Physical Status Classification, smoking history, diabetes status, and amoxicillin allergy. Tooth-level factors included position, presence of restorations, and periodontal conditions with preprosthetic treatments. RESULTS: The results of this study indicate that the patient-level factors significantly associated with tooth retention included age, sex, American Society of Anesthesiologists Physical Classification Status, and amoxicillin allergy. Tooth-level factors such as core buildup, full-coverage crown, healthy periodontium, and scaling and root planing were also associated with higher survival rates. Mandibular premolars had higher survival rates than mandibular molars. CONCLUSIONS: This investigation revealed that the tooth retention rate of endodontically treated teeth was 96.2% after initial root canal treatment, 92.4% for nonsurgical re-treatment, and 97.8% for surgical re-treatment. PRACTICAL IMPLICATIONS: The tooth retention of the endodontic treatment was associated with healthy periodontium, tooth structure, tooth position, tooth restoration, and the patient's overall health.

Laser-Assisted Minimally Invasive Nonsurgical Therapy in Treating Severely Periodontally Compromised Teeth: A Case Series.

Minimally invasive nonsurgical treatment (MINST) aims to remove an etiology with minimal damage to the healthy periodontium and provide the ideal healing environment. This case series introduces the novel protocol of laser-assisted MINST (LAMINST), combining minimally invasive surgery with a dental laser. A total of 25 patients (32 teeth) with advanced periodontal disease were enrolled and received periodontal treatment by following the LAMINST protocol. Probing depth (PD), recession, clinical attachment level (CAL), bleeding on probing (BOP), plaque presence, and site mobility were evaluated preoperatively and at 6 months. Based on the periodontal evaluations, all cases were diagnosed as stage III grade C periodontitis. Six months after LAMINST, the average PD reduction was 4.44 mm and CAL improved by 4.38 mm. Baseline mobility scores of 1 (6 teeth), 2 (9 teeth), and 3 (3 teeth) decreased to 1 (5 teeth) or 0 (13 teeth). The initial prognoses of 5 (hopeless; 15 teeth), 4 (questionable; 13 teeth), and 3 (poor; 4 teeth), improved to 4 (5 teeth), 3 (12 teeth), 2 (fair; 13 teeth), and 1 (good; 2 teeth). The number of BOP sites reduced from 179 to 12, and the number of plaque sites reduced from 173 to 9. All clinical parameters were improved after LAMINST. The application of LAMINST may overcome the traditional limitations of nonsurgical treatment, such as poor accessibility.

SIGHR: Side information guided high-dimensional regression.

In this work, we develop a novel Bayesian regression framework that can be used to complete variable selection in high dimensional settings. Unlike existing techniques, the proposed approach can leverage side information to inform about the sparsity structure of the regression coefficients. This is accomplished by replacing the usual inclusion probability in the spike and slab prior with a binary regression model which assimilates this extra source of information. To facilitate model fitting, a computationally efficient and easy to implement Markov chain Monte Carlo posterior sampling algorithm is developed via carefully chosen priors and data augmentation steps. The finite sample performance of our methodology is assessed through numerical simulations, and we further illustrate our approach by using it to identify genetic markers associated with the nicotine metabolite ratio; a key biological marker associated with nicotine dependence and smoking cessation treatment.

Activated SIRT1 contributes to DPT-induced glioma cell parthanatos by upregulation of NOX2 and NAT10.

Parthanatos is a type of programmed cell death dependent on hyper-activation of poly (ADP-ribose) polymerase 1 (PARP-1). SIRT1 is a highly conserved nuclear deacetylase and often acts as an inhibitor of parthanatos by deacetylation of PARP1. Our previous study showed that deoxypodophyllotoxin (DPT), a natural compound isolated from the traditional herb Anthriscus sylvestris, triggered glioma cell death via parthanatos. In this study, we investigated the role of SIRT1 in DPT-induced human glioma cell parthanatos. We showed that DPT (450 nmol/L) activated both PARP1 and SIRT1, and induced parthanatos in U87 and U251 glioma cells. Activation of SIRT1 with SRT2183 (10 µmol/L) enhanced, while inhibition of SIRT1 with EX527 (200 µmol/L) or knockdown of SIRT1 attenuated DPT-induced PARP1 activation and glioma cell death. We demonstrated that DPT (450 nmol/L) significantly decreased intracellular NAD+ levels in U87 and U251 cells. Further decrease of NAD+ levels with FK866 (100 µmol/L) aggravated, but supplement of NAD+ (0.5, 2 mmol/L) attenuated DPT-induced PARP1 activation. We found that NAD+ depletion enhanced PARP1 activation via two ways: one was aggravating ROS-dependent DNA DSBs by upregulation of NADPH oxidase 2 (NOX2); the other was reinforcing PARP1 acetylation via increase of N-acetyltransferase 10 (NAT10) expression. We found that SIRT1 activity was improved when being phosphorylated by JNK at Ser27, the activated SIRT1 in reverse aggravated JNK activation via upregulating ROS-related ASK1 signaling, thus forming a positive feedback between JNK and SIRT1. Taken together, SIRT1 activated by JNK contributed to DPT-induced human glioma cell parthanatos via initiation of NAD+ depletion-dependent upregulation of NOX2 and NAT10.

TAX1BP1 contributes to deoxypodophyllotoxin-induced glioma cell parthanatos via inducing nuclear translocation of AIF by activation of mitochondrial respiratory chain complex I.

Parthanatos is a type of programmed cell death initiated by over-activated poly (ADP-ribose) polymerase 1 (PARP1). Nuclear translocation of apoptosis inducing factor (AIF) is a prominent feature of parthanatos. But it remains unclear how activated nuclear PARP1 induces mitochondrial AIF translocation into nuclei. Evidence has shown that deoxypodophyllotoxin (DPT) induces parthanatos in glioma cells via induction of excessive ROS. In this study we explored the downstream signal of activated PARP1 to induce nuclear translocation of AIF in DPT-triggered glioma cell parthanatos. We showed that treatment with DPT (450 nM) induced PARP1 over-activation and Tax1 binding protein 1 (TAX1BP1) distribution to mitochondria in human U87, U251 and U118 glioma cells. PARP1 activation promoted TAX1BP1 distribution to mitochondria by depleting nicotinamide adenine dinucleotide (NAD+). Knockdown of TAX1BP1 with siRNA not only inhibited TAX1BP1 accumulation in mitochondria, but also alleviated nuclear translocation of AIF and glioma cell death. We demonstrated that TAX1BP1 enhanced the activity of respiratory chain complex I not only by upregulating the expression of ND1, ND2, NDUFS2 and NDUFS4, but also promoting their assemblies into complex I. The activated respiratory complex I generated more superoxide to cause mitochondrial depolarization and nuclear translocation of AIF, while the increased mitochondrial superoxide reversely reinforced PARP1 activation by inducing ROS-dependent DNA double strand breaks. In mice bearing human U87 tumor xenograft, administration of DPT (10 mg· kg-1 ·d-1, i.p., for 8 days) markedly inhibited the tumor growth accompanied by NAD+ depletion, TAX1BP1 distribution to mitochondria, AIF distribution to nuclei as well as DNA DSBs and PARP1 activation in tumor tissues. Taken together, these data suggest that TAX1BP1 acts as a downstream signal of activated PARP1 to trigger nuclear translocation of AIF by activation of mitochondrial respiratory chain complex I.

Symptomatic secondary spinal arachnoid cysts: a systematic review.

BACKGROUND CONTEXT: Secondary spinal arachnoid cysts have rarely been reported but present significant challenges for management. These cysts could be anteriorly located with long rostral-caudal extensions and many are related to arachnoiditis, leading to difficult-to-treat disorders. Thus far, due to the scarcity of reports, the features of the disease and the optimal therapeutic strategies remain unclear. PURPOSE: To investigate clinical features and the optimal treatment modalities of secondary spinal arachnoid cysts compared with primary spinal arachnoid cysts. STUDY DESIGN: Systematic review. PATIENT SAMPLE: Systematic review identified 103 secondary cases from 80 studies and reports. OUTCOME MEASURES: Condition of symptom relief and duration of treatment response were analyzed. METHODS: An electronic literature search of the PubMed database was conducted for studies on secondary spinal arachnoid cysts between 1990 and 2022. Non-English publications, nonhuman studies, reports of a primary cyst, studies not including case details, and studies of nonsymptomatic cases were excluded. RESULTS: This systematic review included 103 secondary cases. The most commonly reported etiologies were iatrogenic factors, trauma, and subarachnoid hemorrhage, accounting for 88 intradural extramedullary, 11 extradural, one intradural/extradural, one interdural, and one intramedullary spinal arachnoid cyst after a median duration of 30, 12, and 9 months, respectively. Extradural cysts were more prone to occur at dorsal locations and affect thoracic segments (mean cyst length: 3.4 segments). Intradural cysts showed a relatively higher ventral/dorsal ratio (1:1.09, 1.75:1, and 3.50:1 for cysts occurring from iatrogenic factors, trauma, and subarachnoid hemorrhage, respectively) and thoracic distribution, with a mean cyst length of 4.3 segments (5.1 for ventral and 3.5 for dorsal cysts). For intradural cysts, recurrence risk was lower after surgical resection than after fenestration/marsupialization (12-month recurrence risk: 21.43% vs 50.72%, log-rank test: p=.0248, Gehan-Breslow-Wilcoxon test: p=.0126). In cases treated with shunting, one recurrence (1/8 cases) was noted after external shunting and two recurrences (2/5 cases) after internal shunting at a median follow up of 12 months. CONCLUSIONS: Secondary spinal arachnoid cysts, particularly intradural cysts, are rarer and more challenging to treat than primary spinal cysts. Although fenestration/marsupialization is the commonly adopted treatment, the recurrence rate is high. For unresectable cysts, shunting procedures, particularly shunting into a body cavity (eg, pleural or peritoneal cavity) away from the subarachnoid space, could be a therapeutic alternative besides fenestration/marupialization, yet its efficacy requires confirmation by more data.

Multifocal primary amelanotic meningeal melanomas mimicking lymphoma: a case report and literature review.

Primary meningeal melanoma is a rare type of melanocytic cancer originating from the melanocytes of the leptomeninges. It commonly presents as a solitary mass, and multifocal amelanotic lesions were scarcely reported. Diagnosis of multifocal melanoma is particularly challenging, clinically and diagnostically, especially in the absence of cutaneous nevi and melanin pigment. Surgical biopsy result is the gold standard. In this case study, we present an uncommon case of multifocal primary amelanotic meningeal melanomas mimicking lymphomas in the skull base and near the Sylvian fissure, which serves to provide reference value to the clinical diagnosis. Physicians should be aware of the existence of this special type in the clinical work.

Twelve New Seco-Pregnane Glycosides from Cynanchum taihangense.

For our interest in the potential biologically active and structurally unique steroidal glycosides, continued phytochemical investigation of Cynanchum taihangense was carried out; twelve new seco-pregnane glycosides, cynataihosides I-L (1-4), M-T (7-14), and two known glycosides, glaucoside A (5) and atratcynoside F (6), were isolated from the 95% ethanol extract of Cynanchum taihangense. Two new aglycones were found among compounds 10, 11, 13, and 14. The structures of the glycosides were elucidated based on 1D and 2D NMR spectroscopic data, HR-ESI-MS analysis, and chemical evidence. The cytotoxicity of compounds against three human tumor cell lines (HL-60, THP-1, and PC-3) were evaluated by MTT assay. Compound 11 displayed significant cytotoxicity against THP-1 and PC-3 cell line with IC50 values of 5.08 and 22.75 µm, respectively. Compounds 3 and 14 exhibited moderate and selective cytotoxicity on HL-60 and THP-1 with IC50 values of 17.78 and 16.02 µm, respectively.

Lateral ventricle pleomorphic xanthoastrocytoma concurrent with Dandy-Walker complex: A case report.

INTRODUCTION: Dandy-Walker complex and pleomorphic xanthoastrocytomas are both rare disease entities that typically manifest early in life and are associated with congenital etiological factors. Dandy-Walker complex is a cerebellar malformation associated with a series of anatomical changes. The disease onset is usually at birth or during infancy. Late onset in adulthood is uncommon. Pleomorphic xanthoastrocytoma is a rare WHO grade II astrocytic tumor affecting mainly young adults. Concomitant occurrence of Dandy-Walker complex and pleomorphic xanthoastrocytoma has not been previously reported. PATIENT CONCERNS AND DIAGNOSIS: A 30-year-old woman with a previous history of unconfirmed resected lateral ventricle meningioma presented with severe headache for 1 day. Imaging examination revealed a mass in the right lateral ventricle with heterogeneous signal patterns, changes in the posterior fossa corresponding to a Dandy-Walker variant, and mild hydrocephalus. INTERVENTIONS AND OUTCOMES: Surgical complete resection of the mass was achieved. postoperative histopathological examination confirmed WHO grade II pleomorphic xanthoastrocytoma. Three years postsurgery, ventriculoperitoneal shunt was performed due to worsening of hydrocephalus. The patient has since remained symptom-free. CONCLUSION: This is the first report of concomitant occurrence of Dandy-Walker complex and pleomorphic xanthoastrocytoma. The association of neurological congenital malformation with intracranial neoplasms may be multifactorial, with underlying role of genetic mutations or chromosome alterations.

Epidemiology, Characteristic, and Prognostic Factors of Primary Sporadic Intradural Malignant Peripheral Nerve Sheath Tumor in the Spinal Canal: A Systematic Literature Review.

Purpose: Primary sporadic intradural malignant peripheral nerve sheath tumor (MPNST) in the spinal canal is a type of rare neoplasm with challenging diagnosis and therapy. The overall prognosis of this tumor is markedly different from that of the usual spinal intradural tumors. The purpose of this systematic review is to reduce the misdiagnosis and enhance the prognosis of the disease by reviewing the literature. Methods: PubMed, Medline, and Embase databases were searched for articles in English language published from 1980 to May 2021, yielding 500 potentially relevant articles. The keywords were as follows: "spinal", "malignant peripheral nerve sheath tumor", "neurosarcoma", "malignant schwannoma", and "malignant neurofibroma". Thirteen papers met the eligibility criteria, including 55 cases with spinal intradural primary sporadic MPNSTs, which were confirmed by post-operation pathology. We further analyzed the clinical manifestations, radiological manifestations, pathological features, comprehensive treatment strategies, and prognosis. Results: Fifty-five spinal intradural primary sporadic MPNSTs from 30 (54.5%) male and 25 (45.5%) female patients with an average age at diagnosis of 40 years (range, 3-70 years) were included in the study. The most common clinical manifestations were local or radicular pain and motor disturbance. All tumors had significant enhancement and heterogeneous enhancement was more common. Out of 18 lesions, 14 were diagnosed as high grade and the remaining 4 were diagnosed as low grade. The ki-67 labeling index ranged from 5% to 60%. The median recurrence and survival time were 36 and 72 months, respectively. The log-rank tests indicated that significant predictors of OS were patient age (≤30 vs. >30 years) at the time of diagnosis and the presence of metastatic disease, and similar analyses for RFS demonstrated that the presence of metastatic disease was the only significant predictor (60 vs. 10 months). The multivariate Cox proportional hazards regression analysis revealed that absence of metastasis was an independent factor for predicting a favorable prognosis. Conclusions: Spinal intradural primary sporadic MPNSTs are challenging malignant tumors without a systematic treatment plan. The factors affecting its prognosis are not clear. Even after surgical treatment and adjuvant treatment, the recurrence rate and mortality rate are still high. Clinicians should be alert to the possibility of this disease and achieve early detection and treatment.

Neurocutaneous melanosis with an intracranial cystic-solid meningeal melanoma in an adult: A case report and review of literature.

BACKGROUND: Neurocutaneous melanosis (NCM) is a rare congenital, nonhereditary neurocutaneous syndrome that mainly occurs in children; adult NCM is very rare. Due to its rarity, the clinical features and treatment strategies for NCM remain unclear. The purpose of this study was to explore the clinical features, diagnosis, treatment and prognosis of NCM in adults. Most intracranial meningeal melanomas are solid masses, and cystic-solid malignant melanomas are very rare. Due to the lack of data, the cause of cystic changes and the effect on prognosis are unknown. CASE SUMMARY: A 41-year-old woman was admitted to the hospital with intermittent headache for 1 mo. Magnetic resonance imaging (MRI) showed a 4.7 cm × 3.6 cm cystic-solid mass in the left temporal lobe with peritumoral edema. The entire mass was removed, and postoperative pathology indicated malignant melanoma. CONCLUSION: MRI is the first-choice imaging approach for diagnosing central nervous system diseases in NCM patients, although cerebrospinal fluid may also be used. At present, there is no optimal treatment plan; gross total resection combined with BRAF inhibitors and MEK inhibitors might be the most beneficial treatment.

Primary intracranial extraskeletal myxoid chondrosarcoma: A case report and review of literature.

BACKGROUND: Primary intracranial extraskeletal myxoid chondrosarcoma (EMC) is an extremely rare low- to intermediate-grade malignant soft tissue sarcoma, and only 15 cases have been reported in the literature. Due to its rarity, clinical data and research on this tumor type are extremely limited, the pathogenesis and histological origin are still unclear, and the diagnostic and standard clinical treatment strategies for intracranial EMC remain controversial and undefined. CASE SUMMARY: We reported a case of a 52-year-old male who was admitted to the hospital with headache and dizziness for 1 mo, and his health status deteriorated during the last week. CT of the head showed a well-defined low-density lesion situated in the left cavernous sinus. Brain magnetic resonance imaging (MRI) showed a 3.4 cm × 3.0 cm sized, well-defined, round-shaped and heterogeneously enhanced lesion located in the left cavernous sinus. The entire lesion was removed via supratentorial craniotomy and microsurgery. Postoperative pathological diagnosis indicated primary intracranial EMC. Subsequently, the patient underwent 45 Gy/15 F stereotactic radiotherapy after discharge. At present, it is 12 mo after surgery, with regular postoperative follow-up and regular MRI examinations, that there are no clinical symptoms and radiographic evidence indicating the recurrence of the tumor, and the patient has returned to normal life. CONCLUSION: Currently, the most beneficial treatment for primary intracranial EMC is gross total resection combined with postoperative radiotherapy. Long-term follow-up is also necessary for patients.

Malignant Transformation and Metastatic Spread of Dumbbell-Shaped Meningeal Melanocytoma of the Cervical Spine: A Case Report and Literature Review.

Background: Meningeal melanocytoma is a rare disease that originates from leptomeningeal melanocytes in the central nervous system. Meningeal melanocytoma is generally considered benign, and has a good prognosis following complete surgical resection. Reports of the malignant transformation and spread of these tumors are scarce. Case Presentation: A 19 year old female presented with headache, progressive limb weakness, and dyspnea. Magnetic resonance imaging showed a dumbbell-shaped lesion at C1-C2 that was hyperintense on T1 weighted images and showed strong contrast enhancement. Total resection was achieved using a posterior midline approach. Post-operative pathology showed meningeal melanocytoma. The tumor recurred 9 months later with intracranial spread. Resection of the lesion revealed malignant transformation to meningeal melanoma. Conclusion: Meningeal melanocytoma harbors malignant potential even with total resection. Radiotherapy could be considered to prevent disease recurrence and progression.

Coexistent vestibular schwannoma and meningioma in a patient without neurofibromatosis: A case report and review of literature.

BACKGROUND: The simultaneous occurrence of schwannoma and meningioma in the absence of neurofibromatosis (NF) or a previous history of irradiation is exceedingly rare, as only 10 intracranial cases have been reported to date. Herein, we report a case of a coexistent cavernous sinus meningioma and ipsilateral vestibular schwannoma (VS) in a female patient without NF or a history of exposure to irradiation. CASE SUMMARY: A 63-year-old woman presented with progressive left-side hearing loss and tinnitus over the previous year. In the past 6 mo, she developed facial numbness and intermittent headaches. Magnetic resonance imaging showed two lesions that were located on the left side of the cerebellopontine angle and parasellar region. Both lesions were totally resected via the left retrosigmoid approach. Histopathological examination revealed a VS and a meningioma. The patient did not have a family history or clinical or radiological signs of NF. CONCLUSION: The coincident occurrence of VS and meningioma within close vicinity is very rare, and the pathogenesis is unclear. A careful whole-body examination needs to be conducted to exclude NF. Surgical treatment with the goal of total tumor resection is the best therapy. Additional studies are needed for a better understanding of the mechanisms that lead to the development of tumor growth in multiple locations.

Hyperprolactinemia due to pituitary metastasis: A case report.

BACKGROUND: Pituitary metastasis is an uncommon manifestation of systemic malignant tumors. Moreover, hyperprolactinemia and overall hypopituitarism caused by metastatic spread leading to the initial symptoms are rare. CASE SUMMARY: A 53-year-old male patient was admitted to our hospital with complaints of bilateral blurred vision, dizziness, polyuria, nocturia, severe fatigue and somnolence, decreased libido, and intermittent nausea and vomiting for more than 6 mo. During the last 7 d, the dizziness had worsened. Laboratory investigations revealed overall hypofunction of the pituitary gland, but the patient had an elevated serum prolactin level (703.35 mg/mL). Preoperative magnetic resonance imaging revealed a tumor in the sellar region, accompanied by intratumoral hemorrhage and calcification. Thus, transnasal subtotal resection of the lesion in the sellar region was performed. The histopathological and immunohistochemical examinations of the resected lesion revealed metastasis of lung adenocarcinoma to the pituitary gland. Oral hydrocortisone (30 mg/d) and levothyroxine (25 mg/d) were given both pre- and postoperatively. Post-operatively, the clinical symptoms were significantly improved. However, 4 mo following the surgery, the patient succumbed due to multiple organ failure. CONCLUSION: Hyperprolactinemia is one of the markers of poor prognosis in patients with carcinoma that metastasizes to the pituitary gland. Exogenous hormone supplementation plays a positive role in relieving the symptoms of patients and improving quality of life.

Two new pregnane steroidal glycosides from Cynanchum taihangense.

As our ongoing chemical investigation, two new pregnane steroidal glycosides, cynataihosides G (1), with a new aglycone, and H (2) were isolated from the 95% ethanol extract of Cynanchum taihangense. Their structures were elucidated on the basis of 1 D and 2 D NMR spectral data, HR-ESI-MS analysis and qualitative chemical methods. The compounds were subjected to detect the cytotoxicity against three human tumor cell lines (HL-60, THP-1 and PC-3). The compounds displayed no significant cytotoxicity.Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1672682.

Partition Weighted Approach for Estimating the Marginal Posterior Density with Applications.

The computation of marginal posterior density in Bayesian analysis is essential in that it can provide complete information about parameters of interest. Furthermore, the marginal posterior density can be used for computing Bayes factors, posterior model probabilities, and diagnostic measures. The conditional marginal density estimator (CMDE) is theoretically the best for marginal density estimation but requires the closed-form expression of the conditional posterior density, which is often not available in many applications. We develop the partition weighted marginal density estimator (PWMDE) to realize the CMDE. This unbiased estimator requires only a single MCMC output from the joint posterior distribution and the known unnormalized posterior density. The theoretical properties and various applications of the We carry out simulation studies to investigate the empirical performance of the PWMDE and further demonstrate the desirable features of the proposed method with two real data sets from a study of dissociative identity disorder patients and a prostate cancer study, respectively.

2-Methyl-versiquinazoline C, a new fumiquinazoline-type alkaloid from the fungus Aspergillus flavipes PJ03-11.

A new fumiquinazoline-type alkaloid 2-methyl-versiquinazoline C (1), together with six known compounds (2-7), was isolated from Aspergillus flavipes PJ03-11 using OSMAC method. Their structures were elucidated on the basis of extensive spectroscopic analysis, and the absolute configuration of compound 1 was determined by the experimental and calculated ECD data. In addition, the cytotoxic activities against three human cancer cell lines (HL-60, THP-1, and PC-3) were evaluated.

A Bayesian regularized mediation analysis with multiple exposures.

Mediation analysis assesses the effect of study exposures on an outcome both through and around specific mediators. While mediation analysis involving multiple mediators has been addressed in recent literature, the case of multiple exposures has received little attention. With the presence of multiple exposures, we consider regularizations that allow simultaneous effect selection and estimation while stabilizing model fit and accounting for model selection uncertainty. In the framework of linear structural-equation models, we analytically show that a two-stage approach regularizing regression coefficients does not guarantee a unimodal posterior distribution and that a product-of-coefficient approach regularizing direct and indirect effects tends to penalize excessively. We propose a regularized difference-of-coefficient approach that bypasses these limitations. Using the connection between regularizations and Bayesian hierarchical models with Laplace prior, we develop an efficient Markov chain Monte Carlo algorithm for posterior estimation and inference. Through simulations, we show that the proposed approach has better empirical performances compared to some alternatives. The methodology is illustrated using data from two epidemiological studies in human reproduction.

Metformin synergistically enhances the antitumor activity of the third-generation EGFR-TKI CO-1686 in lung cancer cells through suppressing NF-κB signaling.

PURPOSE: Third-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), rociletinib (CO-1686), is great efficacy against EGFR-mutated patients bearing the T790M resistance mutation. However, acquired resistance may emerge. There is a need to characterize acquired resistance mechanism(s) and to devise ways to overcome CO-1686 resistance. EXPERIMENTAL DESIGN: MTT assay, ki67 incorporation assay, transwell assay and TUNEL assay were employed to analyze the effects of metformin to reverse CO-1686 resistance in vitro. The NF-κB activity was measured by the antibody of p50, p65, p-IKBɑ, and p-IKKɑ/ß. Western blotting was used to analyze the proteins in cells. RESULTS: We have established CO-1686-resistant cell lines of PC-9GRCOR and H1975COR from two parental cell lines of PC-9GR and H1975 by long-term exposure to increasing doses of CO-1686. Compared with the parental cells, PC-9GRCOR cells and H1975COR cells showed 90-folds and 20-folds higher resistance to CO-1686, respectively. Critically, we showed that the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling molecular proteins subunits of p50, p65 and its inhibitor proteins of IKBɑ, IKKɑ/ß in phosphorylation levels in resistant cells were higher than parental cells. Accordingly, inhibition of NF-κB activity used TPCA-1 effective in decreasing viability and inducing apoptosis of resistant cells. Moreover, metformin overcame the acquired resistance to CO-1686 by reducing cell proliferation and invasion. Metformin combined with CO-1686 synergistically inhibited the p-IKBɑ, p-IKKɑ/ß, p50, and p65. CONCLUSIONS: NF-κB signaling activation induced acquired resistance to CO-1686. Metformin sensitized resistant cells to CO-1686 via inhibiting NF-κB signaling.