AP-1γ2 is an adaptor protein 1 variant required for endosome-to-Golgi trafficking of the mannose-6-P receptor (CI-MPR) and ATP7B copper transporter.

Selective retrograde transport from endosomes back to the trans-Golgi network (TGN) is important for maintaining protein homeostasis, recycling receptors, and returning molecules that were transported to the wrong compartments. Two important transmembrane proteins directed to this pathway are the Cation-Independent Mannose-6-phosphate receptor (CI-MPR) and the ATP7B copper transporter. Among CI-MPR functions is the delivery of acid hydrolases to lysosomes, while ATP7B facilitates the transport of cytosolic copper ions into organelles or the extracellular space. Precise subcellular localization of CI-MPR and ATP7B is essential for the proper functioning of these proteins. This study shows that both CI-MPR and ATP7B interact with a variant of the clathrin adaptor 1 (AP-1) complex that contains a specific isoform of the γ-adaptin subunit called γ2. Through synchronized anterograde trafficking and cell-surface uptake assays, we demonstrated that AP-1γ2 is dispensable for ATP7B and CI-MPR exit from the TGN while being critically required for ATP7B and CI-MPR retrieval from endosomes to the TGN. Moreover, AP-1γ2 depletion leads to the retention of endocytosed CI-MPR in endosomes enriched in retromer complex subunits. These data underscore the importance of AP-1γ2 as a key component in the sorting and trafficking machinery of CI-MPR and ATP7B, highlighting its essential role in the transport of proteins from endosomes.

Pathologic Processing of Lung Cancer Resection Specimens After Neoadjuvant Therapy.

Neoadjuvant treatment of non-small cell lung cancer challenges the traditional processing of pathology specimens. Induction therapy before resection allows evaluation of the efficacy of neoadjuvant agents at the time of surgery. Many clinical trials use pathologic tumor response, measured as major pathologic response (MPR, ≤10% residual viable tumor [RVT]) or complete pathologic response (CPR, 0% RVT) as a surrogate of clinical efficacy. Consequently, accurate pathologic evaluation of RVT is crucial. However, pathologic assessment has not been uniform, which is particularly true for sampling of the primary tumor, which instead of the traditional processing, requires different tissue submission because the focus has shifted from tumor typing alone to RVT scoring. Using a simulation study, we analyzed the accuracy rates of %RVT, MPR, and CPR of 31 pretreated primary lung tumors using traditional grossing compared with the gold standard of submitting the entire residual primary tumor and identified the minimum number of tumor sections to be submitted to ensure the most accurate scoring of %RVT, MPR, and CPR. Accurate %RVT, MPR, and CPR calls were achieved in 52%, 87%, and 81% of cases, respectively, using the traditional grossing method. Accuracy rates of at least 90% for these parameters require either submission of all residual primary tumor or at least 20 tumor sections. Accurate %RVT, MPR, and CPR scores cannot be achieved with traditional tumor grossing. Submission of the entire primary tumor, up to a maximum of 20 sections, is required for the most accurate reads.

Occult coronary microvascular dysfunction and ischemic heart disease in patients with diabetes and heart failure.

BACKGROUND: Patients with diabetes mellitus (DM) and heart failure (HF) have worse outcomes than normoglycemic HF patients. Cardiovascular magnetic resonance (CMR) can identify ischemic heart disease (IHD) and quantify coronary microvascular dysfunction (CMD) using myocardial perfusion reserve (MPR). We aimed to quantify the extent of silent IHD and CMD in patients with DM presenting with HF. METHODS: Prospectively recruited outpatients undergoing assessment into the etiology of HF underwent in-line quantitative perfusion CMR for calculation of stress and rest myocardial blood flow (MBF) and MPR. Exclusions included angina or history of IHD. Patients were followed up (median 3.0 years) for major adverse cardiovascular events (MACE). RESULTS: Final analysis included 343 patients (176 normoglycemic, 84 with pre-diabetes, and 83 with DM). Prevalence of silent IHD was highest in DM 31% ( 26/83), then pre-diabetes 20% (17/84) then normoglycemia 17%, ( 30/176). Stress MBF was lowest in DM (1.53 ± 0.52), then pre-diabetes (1.59 ± 0.54) then normoglycemia (1.83 ± 0.62). MPR was lowest in DM (2.37 ± 0.85) then pre-diabetes (2.41 ± 0.88) then normoglycemia (2.61 ± 0.90). During follow-up, 45 patients experienced at least one MACE. On univariate Cox regression analysis, MPR and presence of silent IHD were both associated with MACE. However, after correction for HbA1c, age, and left ventricular ejection fraction, the associations were no longer significant. CONCLUSION: Patients with DM and HF had higher prevalence of silent IHD, more evidence of CMD, and worse cardiovascular outcomes than their non-diabetic counterparts. These findings highlight the potential value of CMR for the assessment of silent IHD and CMD in patients with DM presenting with HF.

A Comprehensive Evaluation Algorithm of Multi-Point Relay Based on Link-State Awareness for UANETs.

The Multi-Point Relay (MPR) is one of the core technologies for Optimizing Link State Routing (OLSR) protocols, offering significant advantages in reducing network overhead, enhancing throughput, maintaining network scalability, and adaptability. However, due to the restriction that only MPR nodes can forward control messages in the network, the current evaluation criteria for selecting MPR nodes are relatively limited, making it challenging to flexibly choose MPR nodes based on current link states in dynamic networks. Therefore, the selection of MPR nodes is crucial in dynamic networks. To address issues such as unstable links, poor transmission accuracy, and lack of real-time performance caused by mobility in dynamic networks, we propose a comprehensive evaluation algorithm of MPR based on link-state awareness. This algorithm defines five state evaluation parameters from the perspectives of node mobility and load. Subsequently, we use the entropy weight method to determine weight coefficients and employing the method of Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) for comprehensive evaluation to select MPR nodes. Finally, the Comprehensive Evaluation based on Link-state awareness of OLSR (CEL-OLSR) protocol is proposed, and simulated experiments are conducted using NS-3. The results indicate that, compared to PM-OLSR, ML-OLSR, LD-OLSR, and OLSR, CEL-OLSR significantly improves network performance in terms of packet delivery rate, average end-to-end delay, network throughput, and control overhead.

Evidence of binding between diethylstilbestrol (DES) and the goldfish (Carassius auratus) membrane progesterone receptor α.

BACKGROUND: In a previous study, diethylstilbestrol (DES) was shown to induce oocyte maturation in fish. In the present study, the interaction of DES on goldfish membrane progesterone receptor α (GmPRα) was investigated using a competitive binding assay with radiolabeled steroids. The results indicate that DES exerts its effects on membrane progesterone receptor alpha (mPRα) and induces oocyte maturation through nongenomic steroid mechanisms. This study provides empirical data that demonstrate the binding between DES and GmPRα. METHODS: Binding of DES to GmPRα was achieved by using radiolabeled DES and recombinant GmPRα expressed in culture cells or purified GmPRα proteins that coupled to graphene quantum dots (GQDs). Additionally, the competitive binding of fluorescently labeled progesterone to GmPRα-expressing cells was evaluated. RESULTS: Although significant nonspecific binding of radiolabeled DES to the cell membrane that expresses GmPRα has been observed, specific binding of DES to GmPRα has been successfully identified in the presence of digitonin. Furthermore, the specific binding of DES to GmPRα was confirmed by a binding assay using GQD-GmPRα. The radiolabeled DES was shown to bind to GQD-GmPRα. Additionally, the competition for the binding of fluorescently labeled progesterone to GmPRα-expressing cells was achieved with the DES. CONCLUSIONS: The results of the experiments revealed that DES binds to GmPRα. Thus, it can be concluded that DES induces goldfish oocyte maturation by binding to GmPRα.

[Study on evaluation method of circular small shadow profusion in chest CT reconstruction images of pneumoconiosis].

Objective: To select chest CT image patterns for the diagnosis of pneumoconiosis and establish a method for determining the profusion of circular small shadows in chest CT. Methods: In April 2021, 66 cases of occupational pneumoconiosis patients with digital radiography (DR) chest radiographs and chest CT imaging data with circular small shadow as the main manifestations were selected as the study objects. 1.5 mm and 5 mm chest CT axial images, 1 mm and 5 mm chest CT coronal multi-plane recombination (MPR) images, and 5 mm chest CT coronal maximum intensity projection (MIP) images were used to observe the different characteristics of pneumoconiosis patients, and were compared and analyzed with DR chest radiographs to establish the experimental chest CT standards. The consistency of the profusion results between the experimental chest CT standards and GBZ 70-2015 Diagnosis of Occupational Pneumoconiosis was verified. Results: All the 66 objects were male, including 33 cases of stage Ⅰ pneumoconiosis, 17 cases of stage Ⅱ pneumoconiosis and 16 cases of stage Ⅲ pneumoconiosis. By observing five chest CT images of 66 objects, we found that chest CT images of different modes could clearly display and identify abnormal images such as small circular shadow, large shadow, small shadow aggregation, honeycomb glass shadow, flake glass shadow, uniform low-profusion glass shadow, mesh glass shadow, cable shadow, linear shadow, subpleural spinous shadow, subpleural nodules, various kinds of emphysema and lung texture distortion and fracture. Small shadow aggregation was usually accompanied by the appearance of large shadow. The vascular shadows in 5 mm CT images had good ductility, and small nodules were easy to distinguish. The coronal MIP image of 5 mm chest CT used edge enhancement technology, which was prone to small shadow fusion and fibrotic shadow fusion. The coronal MPR image of 5 mm chest CT was highly consistent with the DR chest radiographs in terms of the integrity of film reading. GBZ 70-2015 standard was used to compare the profusion of DR chest radiographs and 5 mm chest CT coronal MPR images of 66 objects, and the consistency test Kappa=0.64. GBZ 70-2015 standard and experimental chest CT standard were used to compare the profusion results of DR chest radiographs and 5 mm chest CT coronal MPR images of 66 objects, respectively, and the consistency test Kappa=0.80, with high consistency. Conclusion: 5 mm coronal MPR image is suitable for chest CT imaging in the diagnosis of pneumoconiosis. Following the selection path and method of GBZ 70-2015 profusion criterion, the established experimental chest CT standard in determining the profusion of small circular shadows in 5 mm coronal MPR images of chest CT with pneumoconiosis has a high consistency with GBZ 70-2015 standard.

Comparing a PD-L1 inhibitor plus chemotherapy to chemotherapy alone in neoadjuvant therapy for locally advanced ESCC: a randomized Phase II clinical trial : A randomized clinical trial of neoadjuvant therapy for ESCC.

BACKGROUND: A Phase II study was undertaken to evaluate the safety and efficacy of the neoadjuvant socazolimab, a novel PD-L1 inhibitor, in combination with nab-paclitaxel and cisplatin for locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Sixty-four patients were randomly divided between the Socazolimab + nab-paclitaxel + cisplatin (TP) arm (n = 32) and the control arm (n = 32), receiving either socazolimab (5 mg/kg intravenously (IV), day 1) or a placebo with nab-paclitaxel (125 mg/m2 IV, day 1/8) and cisplatin (75 mg/m2 IV, day 1) repeated every 21 days for four cycles before surgery. The primary endpoint was major pathological response (MPR), and the secondary endpoints were pathological complete response (pCR), R0 resection rate, event-free survival (EFS), overall survival (OS), and safety. RESULTS: A total of 29 (90.6%) patients in each arm underwent surgery, and 29 (100%) and 28 (98.6%) patients underwent R0 resection in the Socazolimab + TP and Placebo + TP arms, respectively. The MPR rates were 69.0 and 62.1% (95% Confidence Interval (CI): 49.1-84.0% vs. 42.4-78.7%, P = 0.509), and the pCR rates were 41.4 and 27.6% (95% CI: 24.1-60.9% vs. 13.5-47.5%, P = 0.311) in the Socazolimab + TP and Placebo + TP arms, respectively. Significantly higher incidence rates of ypT0 (37.9% vs. 3.5%; P = 0.001) and T downstaging were observed in the Socazolimab + TP arm than in the Placebo + TP arm. The EFS and OS outcomes were not mature. CONCLUSIONS: The neoadjuvant socazolimab combined with chemotherapy demonstrated promising MPR and pCR rates and significant T downstaging in locally advanced ESCC without increasing surgical complication rates. TRIAL REGISTRATION: Registration name (on clinicaltrials.gov): A Study of Anti-PD-L1 Antibody in Neoadjuvant Chemotherapy of Esophageal Squamous Cell Carcinoma. REGISTRATION NUMBER: NCT04460066.

Association between statin compliance and risk of dementia among patients with chronic periodontitis.

OBJECTIVES: We investigated the association between statin compliance and the risk of dementia among patients with chronic periodontitis. METHODS: Chronic periodontitis patients were extracted from the National Health Insurance Service-Health Screening Cohort Database, covering the period from 2002 to 2019. A total of 22,089 subjects were included in the study and divided into three groups based on their compliance with statin administration. The Cox proportional hazard model was utilized to calculate hazard ratios and 95% confidence intervals for analyzing the risk of dementia. RESULTS: In the restricted cubic spline of the multivariable-adjusted model, the hazard ratio for dementia decreased prominently with a higher medication possession ratio. The hazard ratios and 95% confidence intervals in the multivariable-adjusted model for dementia risk in the middle and high medication possession ratio groups, compared to the low medication possession ratio group, were confirmed as 0.70 (0.57-0.87) and 0.57 (0.45-0.72), respectively. In the subgroup analysis, a significant association between dementia and good statin medication possession ratio was found in both severe periodontitis and mild periodontitis cases. CONCLUSIONS: Our findings suggest that a group of patients with chronic periodontitis who maintain good statin compliance are associated with a reduced risk of dementia.

The impact of a pharmacist-led oral anticancer clinic on medication adherence and laboratory monitoring.

PURPOSE: To evaluate the impact that a pharmacist-managed oral anticancer clinic has on patient adherence to oral anticancer therapy in regard to medication adherence and adherence to lab monitoring. METHODS: A retrospective chart review was completed for patients prescribed abiraterone, enzalutamide, or ibrutinib within the study time period. The primary outcome was assessing medication adherence by comparing the medication possession ratio (MPR) before (Phase 1) and after (Phase 2) initiation of the pharmacist-led oral anticancer therapy clinic. The secondary outcome was assessing lab monitoring adherence by patients and providers in Phase 1 and Phase 2. This will be done by assessing whether labs were ordered at the appropriate time frame by oncology providers, as well as whether or not the patient came and got these labs drawn. This study will also examine outcomes related to the pharmacist-led oral anticancer therapy clinic (phase 2) for descriptive purposes. RESULTS: A total of 189 charts were analyzed with 134 excluded and 55 included (25 patients in phase 1 and 30 patients in phase 2). Independent sample t-test analyses revealed a statistically significant increase (t(30.57) = -1.99; p = 0.027) in the MPR ratio between phase 1 (mean = 0.98, SD = 0.13) compared to phase 2 (mean = 1.04, SD = 0.08). For patient adherence to lab monitoring, there was a statistically significant improvement between phase 1 and phase 2 for patients on abiraterone (21.9% vs 67%; t(25) = -5.73; p < 0.001) and enzalutamide (35.7% vs. 90.5%; t(8) = -3.26; p = 0.006). However, for patients on ibrutinib, there was a slight decline in lab monitoring adherence between phase 1 and phase 2 but this effect was not statistically significant (56.2% vs. 51%; t(17) = 0.58; p = 0.283). Similar results were shown for provider adherence to lab monitoring. Descriptive outcomes showed that the pharmacist had, on average, 6.7 encounters per patient with the majority being phone and face-to-face appointments. CONCLUSIONS: Data from this study demonstrated that a pharmacist-led oral anticancer clinic can improve MPR ratios and patient adherence to oral anticancer medication regimens. In addition, patient and provider lab monitoring adherence was improved for abiraterone and enzalutamide. Improvement in patient and provider lab monitoring adherence for ibrutinib was not shown, possibly due to the impact of the COVID-19 pandemic, relatively small sample size, and retrospective nature of this study. The results of this study support that overall, a pharmacist-led oral anticancer clinic can significantly improve patient outcomes, which aligns with previous smaller studies that have shown similar benefits.

Direct trafficking pathways from the Golgi apparatus to the plasma membrane.

In eukaryotic cells, protein sorting is a highly regulated mechanism important for many physiological events. After synthesis in the endoplasmic reticulum and trafficking to the Golgi apparatus, proteins sort to many different cellular destinations including the endolysosomal system and the extracellular space. Secreted proteins need to be delivered directly to the cell surface. Sorting of secreted proteins from the Golgi apparatus has been a topic of interest for over thirty years, yet there is still no clear understanding of the machinery that forms the post-Golgi carriers. Most evidence points to these post-Golgi carriers being tubular pleomorphic structures that bud from the trans-face of the Golgi. In this review, we present the background studies and highlight the key components of this pathway, we then discuss the machinery implicated in the formation of these carriers, their translocation across the cytosol, and their fusion at the plasma membrane.

Adjuvant tamoxifen adherence in men with early-stage breast cancer.

BACKGROUND: Most breast cancers (BCs) in men are hormone receptor-positive. Adjuvant tamoxifen is part of the standard treatment of these patients. Small, single-institution studies have suggested that men have high rates of discontinuing adjuvant endocrine treatment. The authors examined rates of tamoxifen discontinuation and medication adherence in a large population-based cohort of male patients with BC. METHODS: In the Surveillance, Epidemiology, and End Results-Medicare database, male patients with invasive nonmetastatic BC, diagnosed between 2007 and 2013, who were ≥65 years old, had Part D coverage, and had tamoxifen prescriptions within 1 year of diagnosis were identified. Adherence was defined as a medication possession ratio of ≥80% among those patients who were filling tamoxifen prescriptions. Logistic regression model was used to assess predictors of tamoxifen adherence. RESULTS: A total of 451 patients met eligibility criteria. The median age at diagnosis was 75 years. The median follow-up was 32.5 months. The rates of tamoxifen discontinuation were 15.8%, 24.3%, 31.3%, 36.9%, and 48.3% at 1, 2, 3, 4, and 5 years after diagnosis, respectively. Among the men who were still taking tamoxifen, the corresponding adherence rates were 76.9%, 73.6%, 68.7%, 64.8%, and 60.2%. In the adjusted model, significant predictors of lower adherence included residing in a high poverty area (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.28-2.12) and a Charlson comorbidity score of ≥2 (OR, 0.46; 95% CI, 0.22-0.97). CONCLUSION: Older men with breast cancer have high rates of tamoxifen discontinuation, with 48% of all patients discontinuing tamoxifen before the end of year 5. Additionally, even among those patients continuing tamoxifen, a substantial number of patients are nonadherent. Further research should evaluate potentially modifiable reasons for treatment discontinuation and lack of adherence to tamoxifen.

Acute inactivation of retromer and ESCPE-1 leads to time-resolved defects in endosomal cargo sorting.

Human retromer, a heterotrimer of VPS26 (VPS26A or VPS26B), VPS35 and VPS29, orchestrates the endosomal retrieval of internalised cargo and promotes their cell surface recycling, a prototypical cargo being the glucose transporter GLUT1 (also known as SLC2A1). The role of retromer in the retrograde sorting of the cation-independent mannose 6-phosphate receptor (CI-MPR, also known as IGF2R) from endosomes back to the trans-Golgi network remains controversial. Here, by applying knocksideways technology, we develop a method for acute retromer inactivation. While retromer knocksideways in HeLa and H4 human neuroglioma cells resulted in time-resolved defects in cell surface sorting of GLUT1, we failed to observe a quantifiable defect in CI-MPR sorting. In contrast, knocksideways of the ESCPE-1 complex - a key regulator of retrograde CI-MPR sorting - revealed time-resolved defects in CI-MPR sorting. Together, these data are consistent with a comparatively limited role for retromer in ESCPE-1-mediated CI-MPR retrograde sorting, and establish a methodology for acute retromer and ESCPE-1 inactivation that will aid the time-resolved dissection of their functional roles in endosomal cargo sorting.

Membrane progesterone receptor α (mPRα) enhances hypoxia-induced vascular endothelial growth factor secretion and angiogenesis in lung adenocarcinoma through STAT3 signaling.

Lung cancer remains a huge challenge to public health because of its high incidence and mortality, and lung adenocarcinoma (LUAD) is the main subtype of lung cancer. Hypoxia-induced vascular endothelial growth factor (VEGF) release and angiogenesis have been regarded as critical events in LUAD carcinogenesis. In the present study, membrane progesterone receptor α (mPRα) is deregulated within LUAD tissue samples; increased mPRα contributes to a higher microvessel density (MVD) in LUAD tissues. mPRα knockdown in A549 and PC-9 cells significantly inhibited STAT3 phosphorylation, as well as HIF1α and VEGF protein levels, decreasing cancer cell migration and invasion. The in vivo xenograft model further confirmed that mPRα enhanced the aggressiveness of LUAD cells. Furthermore, mPRα knockdown significantly inhibited hypoxia-induced upregulation in HIF1α and VEGF levels, as well as LUAD cell migration and invasion. Under the hypoxic condition, conditioned medium (CM) derived from mPRα knockdown A549 cells, namely si-mPRα-CM, significantly inhibited HUVEC migration and tube formation and decreased VEGF level in the culture medium. In contrast, CM derived from mPRα-overexpressing A549 cells, namely mPRα-CM, further enhanced HUVEC migration and tube formation and increased VEGF level under hypoxia, which was partially reversed by STAT3 inhibitor Stattic. In conclusion, in LUAD cells, highly expressed mPRα enhances the activation of cAMP/JAK/STAT3 signaling and increases HIF1α-induced VEGF secretion into the tumor microenvironment, promoting HUVEC migration and tube formation under hypoxia.

Pediatric reference values of anterior visual pathway structures measured with axis-correction on high-resolution 3D T2 fast spin echo sequences.

BACKGROUND: The size of the anterior visual pathway (AVP) structures is affected by patient age and pathology. Normative data is useful when determining whether pathology is present. AVP structures do not respect the standard planes of magnetic resonance (MR) imaging. The aim of this study was to produce normative age-related and axis-corrected data of the AVP structures using multiplanar reformation (MPR) of high-resolution 3D T2-weighted fast spin echo (3D T2w FSE) images. METHODS: For each patient 32 measurements of AVP structures were obtained in 145 children (2 months - 18 years) with normal brain MR studies on high-resolution 3D T2w FSE images adjusted to the axis of each AVP structure. Descriptive statistics were calculated for different age classes and growth models were fitted to the data and assessed for their performance to create a formal statistical model that allows inference beyond the sample. RESULTS: Descriptive statistics were compiled in a reference table and prediction plots in relation to age, height, and body surface area (BSA) were obtained from the best overall performing statistical model, also taking field strength (1.5 vs. 3 T) into account. Intraclass correlation coefficient values were calculated for all variables ranging from 0.474 to 0.967, the most reliable being the transverse diameter of the globe, the maximum diameter of the retrobulbar nerve sheath, the intracranial segment of the optic nerve and the transverse diameter of the chiasm. The maximum retrobulbar diameter of the optic nerve sheath and the lateral superoinferior diameter of the chiasm showed no statistically significant change with age. CONCLUSION: Detailed charts of reference values for AVP structures as well as prediction plots in relation to age, height and BSA were established using axis-corrected measurements from the MPR of high-resolution 3D T2w FSE images. Furthermore, an Excel spreadsheet that allows users to calculate normative values for the 9 AVP structures of key interest is provided as supplementary material.

Allopregnanolone: Metabolism, Mechanisms of Action, and Its Role in Cancer.

Allopregnanolone (3α-THP) has been one of the most studied progesterone metabolites for decades. 3α-THP and its synthetic analogs have been evaluated as therapeutic agents for pathologies such as anxiety and depression. Enzymes involved in the metabolism of 3α-THP are expressed in classical and nonclassical steroidogenic tissues. Additionally, due to its chemical structure, 3α-THP presents high affinity and agonist activity for nuclear and membrane receptors of neuroactive steroids and neurotransmitters, such as the Pregnane X Receptor (PXR), membrane progesterone receptors (mPR) and the ionotropic GABAA receptor, among others. 3α-THP has immunomodulator and antiapoptotic properties. It also induces cell proliferation and migration, all of which are critical processes involved in cancer progression. Recently the study of 3α-THP has indicated that low physiological concentrations of this metabolite induce the progression of several types of cancer, such as breast, ovarian, and glioblastoma, while high concentrations inhibit it. In this review, we explore current knowledge on the metabolism and mechanisms of action of 3α-THP in normal and tumor cells.

Involvement of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) in mPRα (PAQR7)-mediated progesterone induction of vascular smooth muscle relaxation.

Progesterone acts directly on vascular smooth muscle cells (VSMCs) through activation of membrane progesterone receptor α (mPRα)-dependent signaling to rapidly decrease cytosolic Ca2+ concentrations and induce muscle relaxation. However, it is not known whether this progesterone action involves uptake of Ca2+ by the sarco/endoplasmic reticulum (SR) and increased sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity. The present results show that treatment of cultured human VSMCs with progesterone and the selective mPR agonist Org OD-02-0 (OD 02-0) but not with the nuclear PR agonist R5020 increased SERCA protein expression, which was blocked by knockdown of mPRα with siRNA. Moreover, treatments with progesterone and OD 02-0, but not with R5020, increased phospholamban (PLB) phosphorylation, which would result in disinhibition of SERCA function. Progesterone and OD 02-0 significantly increased Ca2+ levels in the SR and caused VSMC relaxation. These effects were blocked by pretreatment with cyclopiazonic acid (CPA), a SERCA inhibitor, and by knockdown of SERCA2 with siRNA, suggesting that SERCA2 plays a critical role in progesterone induction of VSMC relaxation. Treatment with inhibitors of inhibitory G proteins (Gi, NF023), MAP kinase (AZD 6244), Akt/Pi3k (wortmannin), and a Rho activator (calpeptin) blocked the progesterone- and OD 02-0-induced increase in Ca2+ levels in the SR and SERCA expressions. These results suggest that the rapid effects of progesterone on cytosolic Ca2+ levels and relaxation of VSMCs through mPRα involve regulation of the functions of SERCA2 and PLB through Gi, MAP kinase, and Akt signaling pathways and downregulation of RhoA activity.NEW & NOTEWORTHY The rapid effects of progesterone on cytosolic Ca2+ levels and relaxation of VSMCs through mPRα involve regulation of the functions of SERCA2 and PLB through Gi, MAP kinase, and Akt signaling pathways and downregulation of RhoA activity.

Canakinumab with and without pembrolizumab in patients with resectable non-small-cell lung cancer: CANOPY-N study design.

Canakinumab is a human IgGκ monoclonal antibody, with high affinity and specificity for IL-1ß. The Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) trial, evaluating canakinumab for cardiovascular disease, provided the first signal of the potential of IL-1ß inhibition on lung cancer incidence reduction. Here, we describe the rationale and design for CANOPY-N, a randomized Phase II trial evaluating IL-1ß inhibition with or without immune checkpoint inhibition as neoadjuvant treatment in patients with non-small-cell lung cancer. Patients with stage IB to IIIA non-small-cell lung cancer eligible for complete resection will receive canakinumab or pembrolizumab as monotherapy, or in combination. The primary end point is major pathological response by central review; secondary end points include overall response rate, major pathological response (local review), surgical feasibility rate and pharmacokinetics. Clinical trial registration: NCT03968419 (ClinicalTrials.gov).

Lay abstract A previous study showed that canakinumab reduced the risk of lung cancer in patients with heart disease. Canakinumab blocks an inflammatory protein called IL-1ß that is involved in cancer. Anti-cancer drugs used before surgery ('neo-adjuvant') can improve the success rate of surgery and may help prevent the cancer from returning. Neo-adjuvant trials help us understand how the drugs work and how they affect cancer. CANOPY-N (NCT03968419) is an ongoing randomized, exploratory, Phase II clinical trial testing canakinumab and pembrolizumab (a different cancer immunotherapy), alone or combined, for patients with early non-small-cell lung cancer. The study will test whether treatment can kill most cancer cells in the surgery sample ('major pathological response'). It will also investigate other effects on cancer biology, levels of molecules that measure possible clinical benefit ('biomarkers') and side effects.

Changes of incudostapedial joint angle in stapedotomy: does it impact hearing outcomes?

PURPOSE: The aims of this article are: (1) is there an ideal incudostapedial joint (ISJ) angle after stapedotomy? (2) is there any difference between pre- and postoperative ISJ angle? and (3) what is the significance of the ISJ angle in postoperative hearing outcomes? METHODS: Forty six ears from 39 different adult patients (28 women and 11 men; 21 left and 25 right ears) with a mean age of 39 years with clinical otosclerosis who underwent stapedotomy between May 2017 and May 2019 were retrospectively registered, including seven bilateral surgery cases. ISJ angle and intravestibular depth of the stapes prosthesis were measured from multiple planar reconstruction-computed tomography images and the length of the prosthesis was measured during surgery. Relationships between the ISJ angle parameters and postoperative hearing outcomes and parameters of the prosthesis were analyzed. RESULTS: The mean ISJ angle was 93.3° ± 8.8° preoperatively and 101.9° ± 6.3° postoperatively, increasing by 8.6° during stapedotomy (p < 0.01). There were weak and negative correlations between ISJ angle changes and postoperative air conduction gains at frequencies ≤1 kHz and bone conduction gains at 0.5 kHz. When the postoperative ISJ angle changed more than 20°, the success rate of the procedure decreased to 0%. CONCLUSION: The stapedotomy operation increased the ISJ angle. The success of postoperative auditory outcomes had more to do with the ISJ angle change than the value of the angle itself, indicating there is no universal ideal ISJ angle that surgeons should aim for during stapedotomy.

Multiple Perpetrator Rape Committed by Female Offenders: A Comparison of Solo, Duo, and 3+ Group Offenders.

Previous studies on multiple perpetrator rapes have shown that male sexual offenders who commit their offense alone differ on offender, offense, and victim characteristics from those who commit their offense in duos and 3+ groups. For the current study, 246 female sexual offenders have been studied regarding their co-offending pattern and the differences in offender, offense, and victim characteristics. Significant differences between solo (n = 73), duos (n = 146), and 3+ group offenders (n = 27) were found for the age at the first conviction, age at the time of the index offense, performed sexual acts, physical and verbal violence, victim gender, victim relationship, victim age, and location where the abuse took place. There were four indicators that could predict the assault type. Co-offenders were more likely than solo offenders to perform penetration on a female, intrafamilial victim who they assaulted indoors. These results have implications for interventions with offenders and criminal justice authorities.

Medication adherence status among patients with neurological conditions and its association with quality of life.

BACKGROUND/AIM: Medication non-adherence may cause significant morbidity and mortality in patients with chronic diseases and may increase the economic burden on the healthcare system. The prevalence of neurological disorders is increasing in Malaysia; however, comprehensive data on medication adherence among Malaysian patients with these disorders is limited. This study was conducted to determine the association of medication non-adherence with quality of life in patients with neurological problems. METHODS: A cross-sectional survey was performed in 370 patients diagnosed with epilepsy, Parkinson's disease, stroke and Alzheimer's disease at Neurology clinic. Patients aged 18 years or older, without documented physical or psychiatric illness such as schizophrenia and major depression, were included. Patient-administered questionnaires, such as the Malaysian Medication Adherence Scale and Medication Possession Ratio were used to determine medication adherence. An established EQ-5D-3L questionnaire was used to determine quality of life. Data were analysed using descriptive and inferential analysis. RESULTS: The overall prevalence of medication non-adherence among patients with neurological disorders was 59.2%. Among these neuromedical diseases, 69.2% (n = 9/13) of Alzheimer's disease, 66.7% (n = 98/147) of epilepsy, 62.1% (n = 36/58) of Parkinson's disease and 48.7% (n = 74/152) of stroke patients were found non-adherent. There was a significant difference in EQ-5D index scores (p = 0.041) between adherent and non-adherent patients. CONCLUSION: A high prevalence of medication non-adherence was found among patients with neurological disorders. The rate of non-adherence varied among different neurological conditions. There was a significant difference in quality of life between adherent and non-adherent patients.