N-glycosylation on Asn-57 is required for the correct HAI-2 protein folding and protease inhibitory activity.

Hepatocyte growth factor activator inhibitor (HAI)-2 is an integral membrane Kunitz-type serine protease inhibitor that regulates the proteolysis of matriptase and prostasin in a cell-type selective manner. The cell-type selective nature of HAI-2 function depends largely on whether the inhibitor and potential target enzymes are targeted to locations in close proximity. The N-glycan moiety of HAI-2 can function as a subcellular targeting signal. HAI-2 is synthesized with 1 of 2 different N-glycan modifications: one of oligomannose-type, which largely remains in the endoplasmic reticulum/GA, and another of complex-type, which is targeted toward the apical surface in vesicle-like structures, and could function as an inhibitor of matriptase and prostasin. HAI-2 contains 2 putative N-glycosylation sites, Asn-57 and Asn-94, point mutations of which were generated and characterized in this study. The protein expression profile of the HAI-2 mutants indicates that Asn-57, and not Asn-94, is responsible for the N-glycosylation of both HAI-2 species, suggesting that the form with oligomannose-type N-glycan is the precursor of the form with complex-type N-glycan. Unexpectedly, the vast majority of non-glycosylated HAI-2 is synthesized into multiple disulfide-linked oligomers, which lack protease inhibitory function, likely due to distorted conformations caused by the disarrayed disulfide linkages. Although forced expression of HAI-2 in HAI-2 knockout cells artificially enhances HAI-2 oligomerization, disulfide-linked HAI-2 oligomers can also be observed in unmodified cells. These results suggest that N-glycosylation on Asn-57 is required for folding into a functional HAI-2 with full protease suppressive activity and correct subcellular targeting signal.

A phase II randomised trial of induction chemotherapy followed by concurrent chemoradiotherapy in locally advanced pancreatic cancer: the Taiwan Cooperative Oncology Group T2212 study.

BACKGROUND: The objective of this study was to evaluate the efficacy and safety of induction chemotherapy (ICT), GOFL (gemcitabine, oxaliplatin plus fluorouracil (5-FU)/leucovorin) versus modified FOLFIRINOX (irinotecan, oxaliplatin plus 5-FU/leucovorin), followed by concurrent chemoradiotherapy (CCRT) in locally advanced pancreatic adenocarcinoma (LAPC). METHODS: Chemo-naive patients with measurable LAPC were eligible and randomly assigned to receive biweekly ICT with either mFOLFIRINOX or GOFL for 3 months. Patients without systemic progression would have 5-FU- or gemcitabine-based CCRT (5040 cGy/28 fractions) and were then subjected to surgery or continuation of chemotherapy until treatment failure. The primary endpoint was 9-month progression-free survival (PFS) rate. RESULTS: Between July 2013 and January 2019, 55 patients were enrolled. After ICT, 21 (77.8%) of 27 patients who received mFOLFIRINOX and 17 (60.7%) of 28 patients who received GOFL completed CCRT. Of them, one and five had per-protocol R0/R1 resection. On intent-to-treat analysis, the 9-month PFS rate, median PFS and overall survival in mFOLFIRINOX and GOFL arms were 30.5% versus 35.9%, 6.6 (95% confidence interval: 5.9-12.5) versus 7.6 months (3.9-12.3) and 19.6 (13.4-22.9) versus 17.9 months (13.4-23.9), respectively. Grade 3-4 neutropenia and diarrhoea during induction mFOLFIRINOX and GOFL were 37.0% versus 21.4% and 14.8% versus 3.6%, respectively. CONCLUSION: Induction GOFL and mFOLFIRINOX followed by CCRT provided similar clinical outcomes in LAPC patients. GOV IDENTIFIER: NCT01867892.

Association of red blood cell size and physical fitness in a military male cohort: The CHIEF study.

Anemia manifested as reduced red blood cell (RBC) amounts or hemoglobin levels has been associated with lower cardiorespiratory fitness. However, the relationship of smaller RBC with physical fitness was unknown. We included 2933 non-anemic military males (hemoglobin levels: 11.1-15.9 g/dL and mean corpuscular volume (MCV) <100 fL) in Taiwan during 2014. Aerobic fitness was assessed by time for a 3000-meter run, and anaerobic fitness was evaluated by numbers of sit-ups and push-ups, each performed within 2 minutes. Multiple linear and logistic regression models adjusting for age, service specialty, lipid profiles, and hemoglobin levels were used to determine the associations. Microcytosis and normocytosis were defined as MCV ≤ 70 fL (n = 190) and MCV > 70 fL (n = 2743), respectively. The linear regression shows that as compared with microcytosis, normocytosis was associated with more numbers of sit-ups performed within 2 minutes (ß = 1.51, P-value = 0.02). The logistic regression also reveals that those males with microcytosis had higher probability as the worst 10% performers in the 2-minute push-up test (odds ratio: 1.91, 95% confidence intervals: 1.18-3.12). By contrast, there was no association of microcytosis with 3000-meter running time. Our study suggests that non-anemic microcytosis was associated with lower anaerobic fitness but not with aerobic fitness. Whether the causative factors for microcytosis such as iron deficiency status and thalassemia trait unavailable in the study might account for the relationship needs further investigations.

Charlson comorbidity index predicts outcomes of elderly after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND/PURPOSE: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the curative therapy for acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), but advanced age with multiple comorbidities limits the eligibility for allo-HSCT. We conducted a retrospective study to investigate the comorbidities assessments and prognostic factors that predict outcomes for these patients. METHODS: Clinical data of patients older than 50 years who had received diagnoses of AML or MDS and underwent allo-HSCT were obtained. Information on patient characteristics, including age, gender, allogeneic transplant type, conditioning regimens, Charlson comorbidity index (CCI), and presence of acute graft-versus-host disease (GVHD) or chronic GVHD, were collected and analyzed. RESULTS: Two hundred fifty-five elderly patients with a median age at allo-HSCT of 57 years were included. The significant prognostic factors associated with worse overall survival (OS) were CCI ≥3 (hazard ratio: 1.88) and grade III-IV acute GVHD (3.18). Similar findings were noted in the non-relapse mortality analysis. To investigate the effects of chronic GVHD on patient outcomes, OS analysis was performed for those with survival >100 days after transplantation. The results revealed CCI ≥3 (1.88) and grade III-IV acute GVHD (2.73) remained poor prognostic factors for OS, whereas mild chronic GVHD (0.43) was associated with better OS. CONCLUSION: This cohort study suggests that CCI ≥3 predicts poor outcomes, primarily due to a higher NRM risk. Careful management of GVHD after transplantation could improve outcomes in elderly patients with AML or MDS after allo-HSCT.

The treatment outcome of multiple myeloma patients ineligible for hematopoietic transplantation--a single institutional experience in Taiwan.

Multiple myeloma (MM) is characterized by the neoplastic proliferation of monoclonal plasma cells in the bone marrow and results in complications. In Taiwan, melphalan and several novel agents are used to treat myeloma patients who are not candidate for hematopoietic stem cell transplant (HSCT). This retrospective study aimed to evaluate the characteristics, treatment outcome, and prognostic factors of MM patients who were ineligible for HSCT at our institution from October 2000 until November 2012. A total of 101 MM patients were reviewed. The median age was 71.0 years, and median overall survival (OS) was 22.0 months. Most of patients were diagnosed as IgG-type myeloma (55.4 %). The initial presentations included anemia (89.1 %), skeletal events (49.5 %), severe renal insufficiency (30.7 %), and hypercalcemia (28.7 %). With regard to the frontline therapy, thalidomide/steroid was the most common. Infection was the leading cause of death and adverse effects. Treatment with bortezomib, almost in the second- or third-line setting, was associated with longer median OS (35.5 months) and the median time to progression (TTP) (6.0 months). Bortezomib treatment, chemotherapy, International Staging System (ISS) stage I, and better performance status significantly correlated with survival benefit. In the bortezomib-treated subgroup, better treatment response caused excellent median OS (67.7 months) and also significantly delayed TTP. Therefore, this current analysis concluded a median OS of 22 months in myeloma patients ineligible for HSCT at our institution during the past 10 years. The use of bortezomib with better treatment response also achieved significantly better median OS and TTP.

The correlation between a chronic inflammatory marker Tartrate-resistant acid phosphatase 5a with cancer cachexia.

PURPOSE: The mechanism of cancer cachexia remains unclear and inflammatory cytokines may play a role in its development. Interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor-α (TNFα) are known to be associated with cancer cachexia. Tartrate-resistant acid phosphatase 5a (TRACP5a) is proposed to be related to chronic inflammation. In this study we hypothesize that TRACP5a is a chronic inflammatory marker that is correlated with cancer cachexia. METHODS: Fifty-five cancer patients with and without cancer cachexia were enrolled from January 2009 to December 2012. Body mass index (BMI) was measured and serum total cholesterol, triglycerides and albumin were examined to evaluate the nutritional status. IL-6, CRP and TRACP5a protein activity were evaluated. RESULTS: Inflammatory markers including IL-6, and CRP were significantly elevated in patients with cancer cachexia (p=0.0075 and 0.0021, respectively). Patients with cachexia also had higher CRP/albumin ratio (p=0.0265). TRACP5a activity, TRACP5a protein and their combinations with albumin were increased in the cancer cachexia groups but without significant difference. There were good correlations between IL-6, CRP, and BMI. Patients with higher TRACP5a activity had shorter survival (p=0.004). CONCLUSION: TRACP5a may be a promising chronic inflammatory marker and may play a prognostic role in cancer cachexia. Further large-scale prospective studies are warranted to confirm its role in the cancer cachexia process.

Gefitinib as first-line treatment for patients with epidermal growth factor receptor-mutated advanced lung adenocarcinoma: a single institution experience in Taiwan.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent a new treatment option for patients with advanced lung adenocarcinoma. In this article we assessed the treatment response and tried to identify prognostic factors which may provide some information different from previously published reports in groups with better performance status (PS) than our enrolled patients. METHODS: The records of 85 patients with EGFR-mutated advanced lung adenocarcinoma who received gefitinib 250 mg once daily as front-line monotherapy between October 2007 and October 2012 were analysed. Direct sequencing methods were used for detecting EGFR mutations. SPSS (version 20) software was used for all data analysis. RESULTS: The median overall survival (OS) and progression free survival (PFS) were 25.6 and 6.9 months, respectively. No statistical significance between the two groups of exon 19 and exon 21 in OS and PFS was registered (p=0.414 and p=0.519, respectively). The group of patients treated > 3 months had a better median OS survival compared with those treated < 3 months (25.6 vs 4.9 months, p<0.001). In multivariate analysis, significant benefit on OS was observed in patients with ECOG PS scores of 0-2 (p=0.002) and those treated for longer time periods (p<0.001), rather than age, sex and smoking. Among the adverse effects (AEs), skin manifestation was correlated with significantly better OS (p=0.007) but insignificant effect on PFS (p=0.131). CONCLUSIONS: Good ECOG PS, longer TKI use and skin rash were significant factors predictive for gefitinib antitumor activity.

Heterogenous liver parenchymal enhancement in CT is a favorable prognosis of HCC after hepatic resection.

This study aimed to define the role of heterogeneity of liver parenchymal enhancement on computed tomography (CT) in the survival of patients with hepatocellular carcinoma (HCC) after hepatic resection. The medical records of patients with HCCs and who had undergone hepatic resection were retrospectively reviewed. The standard deviation (SD) of three different enhanced CT scan images was used to estimate the heterogeneity of liver parenchymal enhancement: SD of > 5.6, heterogenous enhancement, and SD of ≤ 5.6, homogeneous enhancement. A total of 57 patients had heterogenous enhancement, and 143 patients had homogeneous enhancement. The patients with heterogenous enhancement had longer disease-free and overall survivals than those with other enhancements (log-rank test, P < 0.001 and P = 0.036). The pathologic exam showed that heterogenous enhancement tended to develop septa in the peritumoral liver tissues. The prevalence of CD8+ cells was significantly higher in the peritumor liver tissues with septa than in those without (0.83% vs. 0.26%, P < 0.001). The peritumoral CD8/Foxp3 ratio was higher in the liver tissues with septa than in those without (1.22 vs. 0.47, P = 0.001), and patients with CD8/Foxp3 of > 0.8 had better overall survival than those with CD8/Foxp3 of ≤ 0.8 (log-rank test, P = 0.028). In conclusion, patients who had undergone hepatic resection with a heterogenous liver parenchymal enhancement tended to develop hepatic septa, which was associated with a higher CD8/Foxp3 ratio and longer survival. Therefore, contrast-enhanced CT scans might be a useful tool to predict the outcome of HCC.

Administration of gemcitabine and cisplatin in cancer patients with renal failure under hemodialysis.

PURPOSE: There is no optimal dosing schedule of gemcitabine (GEM) and cisplatin (CDDP) combination for cancer patients with renal failure (RF) on hemodialysis (HD). The purpose of this study was to share our experience of using GEM and CDDP in such patients. METHODS: The starting dose of GEM was defined based on single-agent treatment of two cancer patients with RF. Between November 2006 and June 2009, 4 RF cancer patients on HD received a GEM and CDDP combination chemotherapy (CDDP 30mg/m(2) on days 1, 8, 15 and GEM 600mg/m(2) on day 15; repeated every 28 days). The HD was conducted within 24 hours after the completion of GEM and/or CDDP administration. RESULTS: Reduced-dose GEM and CDDP combination showed efficacy and good tolerability for cancer patients with RF under HD.

Effects of Psychiatric Disease Severity and Clinical Characteristics on Duration of High Violence Risk: A Perspective on Violence Prevention in the Psychiatric Ward.

Objective: Prevention, de-escalation, and management of violence in the acute psychiatric ward is essential. Few studies have focused on differences in the duration of high-violence risk between different profiles of high-violence risk. This study aimed to analyze the data of high-violence patients and duration of high-violence risk to provide a new perspective on violence prevention, de-escalation and management. Methods: This retrospective observational cohort study included 171 patients who were treated in the acute psychiatric ward of Keelung Chang Gung Memorial Hospital between January 2016 and June 2020, and who were assessed daily as having high violence risk. All patient data were collected from electronic hospital records (eg, age, gender, diagnosis, violence history, self-harm history, and admission condition (involuntary admission, discharged against medical advice). Between-group differences in disease severity, use of antipsychotics and benzodiazepine, and duration of high violence risk were analyzed using regression analysis. Results: Only patients' age was significantly associated with duration of high-violence risk (P = 0.028), making it predictive of longer duration of high-violence risk. In patients with schizophrenia spectrum disorder or bipolar disorder, higher severity was significantly associated with longer duration of high-violence risk (P = 0.007, P = 0.001, respectively). Conclusion: Only age is a predictor of longer duration of violence risk in psychiatric patients, although higher severity is associated with higher violence risk. Study results may help management and healthcare staff better understand how quickly or slowly violence risk will decrease and may improve efficient use of healthcare resources and individualized patient-centered care.

Cholecystoenteric fistula in a patient with advanced gallbladder cancer: A case report and review of literature.

BACKGROUND: Cholecystoenteric fistula (CEF) involves the formation of a spontaneous anomalous tract between the gallbladder and the adjacent gastrointestinal tract. Chronic gallbladder inflammation can lead to tissue necrosis, perforation, and fistulogenesis. The most prevalent cause of CEF is chronic cholelithiasis, which rarely results from malignancy. Because the symptoms and laboratory findings associated with CEF are nonspecific, the condition is often misdiagnosed, presenting a challenge to the surgeon when detected intraoperatively. Therefore, a preoperative diagnosis of CEF is crucial. CASE SUMMARY: We present the case of a 57-year-old male with advanced gallbladder cancer (GBC) who arrived at the emergency room with persistent vomiting, abdominal pain, and diarrhea. An abdominopelvic computed tomography scan revealed a contracted gallbladder with bubbles in the fundus connected to the second portion of the duodenum and transverse colon. We suspected that GBC had invaded the adjacent gastrointestinal tract through a cholecystoduodenal fistula (CDF) or a cholecystocolonic fistula (CCF). He underwent multiple examinations, including esophagogastroduodenoscopy, an upper gastrointestinal series, colonoscopy, and magnetic resonance cholangiopancreatography; the results of these tests confirmed a diagnosis of synchronous CDF and CCF. The patient underwent a Roux-en-Y gastrojejunostomy and loop ileostomy to address the severe adhesions that were previously observed to cover the second portion of the duodenum and hepatic flexure of the colon. His symptoms improved with supportive treatment while hospitalized. He initiated oral targeted therapy with lenvatinib for further anticancer treatment. CONCLUSION: The combination of imaging and surgery can enhance preoperative diagnosis and alleviate symptoms in patients with GBC complicated by CEF.

Drug-eluting beads loaded with irinotecan to treat synchronous liver-only metastases of colorectal cancer non-responsive to bevacizumab-based chemotherapy.

OBJECTIVE: To evaluate the efficacy of drug-eluting beads loaded with irinotecan (DEBIRI) in colorectal cancer (CRC) patients with synchronous liver-only metastases non-responsive to bevacizumab-based chemotherapy (BBC). METHODS: Fifty-eight patients were enrolled in this study. Treatment response to BBC and DEBIRI were determined by the morphological criteria and Choi's criteria, respectively. Progression-free survival (PFS) and overall survival (OS) were recorded. The correlation between pre-DEBIRI CT parameters and treatment response to DEBIRI was analyzed. RESULTS: CRC patients were divided into the BBC responsive group (R group) (n = 16) and the non-responsive group (n = 42), which was further divided into the NR group (23 patients who did not receive DEBIRI) and the NR+DEBIRI group (19 patients who received DEBIRI after failing BBC). Among the R, NR and NR+DEBIRI groups, the median PFS were 11, 12, and 4 months, respectively (p < 0.01); median OS were 36, 23, and 12 months, respectively (p = 0.01). In the NR+DEBIRI group, 33 metastatic lesions were treated with DEBIRI, of which 18 (54.5%) reached objective response. The receiver operating characteristic curve showed that the contrast enhancement ratio (CER) before DEBIRI could predict objective response (AUC = 0.737, p < 0.01). CONCLUSION: In CRC patients, DEBIRI can achieve acceptable objective response for liver metastases non-responsive to BBC. However, this locoregional control does not prolong survival. The pre-DEBIRI CER can predict OR in these patients. ADVANCES IN KNOWLEDGE: DEBIRI can act as an acceptable locoregional management in CRC patients with liver metastases non-responsive to BBC, and the pre-DEBIRI CER is a potential indicator of locoregional control.

Rapid identification of heterozygous or homozygous JAK2(V617F) mutations in myeloproliferative neoplasms using melting curve analysis.

BACKGROUND/PURPOSE: The activating JAK2 mutation with a G-C to T-A transversion at codon 617 (JAK2(V617F)) is associated with myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis. Here, we report a technical advance in the diagnosis of JAK2(V617F) in MPNs by melting curve analysis (MCA). METHODS: From January through December 2006, we prospectively enrolled 78 patients with PV (n = 21), ET (n = 32), myelofibrosis (n = 5), secondary erythrocytosis (n = 4), secondary thrombocytosis (n = 2), acute myelocytic leukemia (n = 4), chronic myelocytic leukemia (n = 8), and myelodysplastic syndrome (n = 2). Mutation analysis for JAK2(V617F) was performed on either bone marrow or peripheral blood cells using allele-specific polymerase chain reaction (AS-PCR) or sequencing and fluorescence resonance energy transfer (FRET) probes with MCA. RESULTS: For the initial 30 samples, the detection rate of JAK2(V617F) using MCA was comparable to the gold standard of the PCR sequencing methods. However, the turnaround times for MCA and PCR were 2 hours and 2 days, respectively. The detection rate of JAK2(V617F) was 76.2% for PV (homozygous in 14.3%), 46.9% for ET, 80% for myelofibrosis (homozygous in 20%), and 0% for the other conditions. In PV, patients with homozygous JAK2(V617F) presented with significantly longer disease durations than heterozygous patients. In ET, there were no differences in the clinical parameters of patients harboring JAK2(V617F) compared with those with wild-type JAK2. CONCLUSION: Heterozygous and homozygous JAK2(V617F) mutations can be identified using the rapid and reliable assay based on FRET probes and MCA. Detection of JAK2(V617F) can be used to assist in the diagnosis of BCR/ABL-negative MPNs.

Osimertinib-related liver injury with successful osimertinib rechallenge: A case report.

Osimertinib is approved as the first-line treatment for advanced non-small cell lung cancer patients with epidermal growth factor (EGFR) mutation and for patients who develop EGFR T790M mutation during EGFR tyrosine kinase inhibitor (TKI) treatment and disease progression. Asymptomatic elevation of aminotransferase levels is commonly observed during TKI treatment; however, significant hepatotoxicity is infrequent. Here, we report a patient with osimertinib-related drug-induced liver injury who was successfully managed with osimertinib rechallenge.

Modified-Dose Pembrolizumab and Prognostic Outcomes among Non-Small Cell Lung Cancer Patients: A Chart Review Study.

The modified dose (MD) regimen of pembrolizumab (2 mg/kg or 100 mg every 3 weeks) is an alternative option to reduce the financial burden resulting from the extremely high cost of the standard dose (SD) regimen (200 mg every 3 weeks). However, the clinical effectiveness and prognostic outcomes have not been fully elucidated in real-word clinical practice. Sixty-four consecutive patients in Taiwan receiving pembrolizumab for advanced NSCLC between 2018 and 2020 were recruited in this study. Comparisons of overall survival (OS) and progression-free survival (PFS) were performed using Kaplan−Meier survival curves. Additionally, 12 predictors, including pembrolizumab regimen, dose, neutrophil-to-lymphocyte ratio (NLR), age, sex, histopathology, smoking history, ECOG PS, EGFR mutation, PD-L1 expression, distant metastases and treatment line, were analyzed in multivariable Cox models for predicting OS and PFS. The results showed that the MD group and the SD group had similar OS and PFS, especially in patients beyond first-line treatment or with a pretreatment NLR < 5. The NLR was the only independent factor associated with both OS (adjusted HR = 0.052; p = 0.010) and PFS (adjusted HR = 0.259; p = 0.021). The results of this study assure the clinical effectiveness of MD pembrolizumab and suggest that the pretreatment NLR could highlight patients who may benefit from MD pembrolizumab.

Combination therapy of sorafenib and drug-eluting bead transarterial chemoembolization for advanced hepatocellular carcinoma with and without hepatic arteriovenous shunt.

BACKGROUND: To compare the efficacy and safety of combination therapy with sorafenib and drug-eluting bead transarterial chemoembolization (DEB-TACE) in advanced hepatocellular carcinoma (HCC) with or without hepatic arteriovenous shunt (HAVS). METHODS: This retrospective, single-center study enrolled 59 advanced HCC patients treated with combination therapy, of whom 33 (55.9%) patients had HAVS. Tumor response according to the mRECIST criteria was evaluated based on the CT images 1 month after TACE, and changes in the arterial enhancement ratio (AER) of tumors and portal vein tumor thrombosis were also documented. Time-to-progression (TTP), overall survival (OS), and prognostic factors were analyzed. Safety was evaluated with the incidence of TACE-related complications within 6 weeks after TACE. RESULTS: The tumor response between the two groups showed no significant difference in the objective response rate (69.2% in the group without HAVS vs 60.6% in the group with HAVS, p = 0.492) or disease control rate (92.3% vs 87.9%, p = 0.685). The two groups showed comparable TTP (4.23 vs 2.33 months, p = 0.235) and OS (12.77 vs 12.97 months, p = 0.910). A drop in the AER of tumors of more than 20% on post-TACE CT independently predicted better OS. With regard to safety, there was no significant difference between the two groups. CONCLUSION: For advanced HCC, combination therapy had equal efficacy and safety in patients with HAVS compared to those without HAVS, indicating that DEB-TACE is an optional and effective treatment in these patients.

The difference in the intracellular Arg/Lys-rich and EHLVY motifs contributes to distinct subcellular distribution of HAI-1 versus HAI-2.

The integral membrane, Kunitz-type, serine protease inhibitors, HAI-1 and HAI-2, closely resemble one another structurally and with regard to their specificity and potency against proteases. Structural complementarity between the Kunitz domains and serine protease domains renders the membrane-associated serine proteases, matriptase and prostasin, the primary target proteases of the HAIs. The shared biochemical enzyme-inhibitor relationships are, however, at odds with their behavior at the cellular level, where HAI-1 appears to be the default inhibitor of these proteases and HAI-2 a cell-type-selective inhibitor, even though they are widely co-expressed. The limited motility of these proteins caused by their membrane anchorages may require their co-localization within a certain distance to allow the establishment of a cellular level functional relationship between the proteases and the inhibitors. The differences in their subcellular localization with HAI-1 both inside the cell and on the cell surface, compared to HAI-2 predominately in intracellular granules has, therefore, been implicated in the differential manner of their control of matriptase and prostasin proteolysis. The targeting signals present in the intracellular domains of the HAIs are systematically investigated herein. Studies involving domain swap and point mutation, in combination with immunocytochemistry and cell surface biotinylation/avidin depletion, reveal that the different subcellular localization between the HAIs can largely be attributed to differences in the intracellular Arg/Lys-rich and EHLVY motifs. These intrinsic differences in the targeting signal render the HAIs as two independent rather than redundant proteolysis regulators.

Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors.

BACKGROUND: Combination therapy with the administration of GW5074 and sorafenib significantly induced necrotic death in various cancer cells in vivo, as well as prolonging the survival of an animal disease model due to significant suppression of the primary and metastatic lesions. We sought to determine the safety, tolerability, pharmacokinetics, and anti-tumor activity of this co-administration therapy in patients with refractory advanced solid cancers. METHODS: Twelve patients were enrolled. Eligible subjects received different dosages of GW5074 in one of the three dose cohorts (Cohort 1: 750 mg daily, Cohort 2: 1500 mg daily, Cohort 3: 750 mg twice daily) plus 200 mg of sorafenib daily to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) at phase 1. Furthermore, the expression level of phosphorylated DAPKS308 in primary tumor, metastatic tumor, and circulating tumor cells (CTC) were evaluated to investigate the relationship between biomarker and the efficacy profile. RESULTS: Among the 12 enrolled patients in this phase 1 trial, most adverse effects (AE) were grade 1, with two being grade 3. The most frequent AE of all grades were weight loss and hypertension, occurring in 16.7% of participants. Eight patients (66.7%) had the disease controlled by receiving co-administration therapy of GW5074 and sorafenib. GW5074 was found to have poor absorption, as increasing the dosage did not result in a significant increase in the bioavailability of GW5074 in subjects. Furthermore, the expression level of phosphorylated DAPKS308 in tumor and CTCs were correlated with the disease control rate (DCR) and duration of response (DOR). CONCLUSIONS: Co-administration therapy of GW5074 and sorafenib demonstrated a favorable safety profile and showed anti-tumor activity in a variety of tumor types. However, the solubility of GW5074 is not satisfactory. A future phase 2a trial will be carried out using the new salted form that has been proven to be more effective.

Preventing chemotherapy-induced hepatitis B reactivation in breast cancer patients: a prospective comparison of prophylactic versus deferred preemptive lamivudine.

PURPOSE: Prophylactic lamivudine to prevent chemotherapy-induced hepatitis B virus (HBV) reactivation has been widely adopted in hematological cancer patients. We examined the deferred preemptive strategy, upon rising viremia, in breast cancer (BC) patients based on sensitive serum HBV DNA level monitoring in a non-randomized controlled study. PATIENTS AND METHODS: Baseline virological profiles before cytotoxic chemotherapy were retrospectively analyzed in historical BC and non-BC patients. A prospective cohort study, including 22 early BC patients (Group I) who were hepatitis B surface antigen (HBsAg)± and required adjuvant chemotherapy, were enrolled and had deferred preemptive use of lamivudine upon viremic surge. During the study period, another 23 BC patients, who did not participate in the above-mentioned study, received prophylactic use of lamivudine as routine practice (Group 2). Chemotherapy-induced hepatitis events and the lamivudine treatment course were compared. RESULTS: There was no significant difference in the incidence of hepatitis during chemotherapy between these two groups. Patients in Group I had statistically significant shorter duration of lamivudine use during chemotherapy. However, once lamivudine had been initiated, the treatment course is not significantly shorter than those patients given prophylactically. CONCLUSIONS: Deferred preemptive strategy is feasible to control HBV replication and prevent its reactivation in BC patients undergoing chemotherapy. However, it may not be superior to prophylactic strategy and clinically practical.

Association of Obstructive Sleep Apnea With the Risk of Male Infertility in Taiwan.

Importance: Obstructive sleep apnea (OSA) has been proposed as a risk factor in infertility. However, to date, the association between OSA and male infertility has not been examined in a population-based study. Objective: To investigate the risk factor of OSA in male infertility and the outcome of OSA treatment for the risk of male infertility. Design, Setting, and Participants: This case-control population-based study collected data from the Longitudinal Health Insurance Database, a subset of the National Health Insurance Research Database in Taiwan. Male patients with a diagnosis of infertility and at least 3 outpatient visits or 1 hospitalization between January 1, 2000, and December 31, 2013, were included and matched by age, sex, and date of infertility diagnosis with individuals without an infertility diagnosis. Data analysis was performed from October 22, 2018, to April 22, 2019. Exposures: Patients with male infertility and randomly selected patients without male infertility were matched using a 1:4 propensity score matching ratio. Main Outcomes and Measures: A primary outcome was the risk factor of OSA (diagnosed through polysomnography). A secondary outcome was the association of the risk of male infertility with OSA exposure time interval (short term, middle term, and long term) and OSA management (ie, none, continuous positive airway pressure, uvulopalatopharyngoplasty, or both). Results: A total of 4607 male patients with infertility (mean [SD] age, 34.18 [5.44] years) and 18 428 control patients (mean [SD] age, 34.28 [5.81] years) were included. In the multivariate conditional logistic regression analysis, OSA was an independent risk factor associated with infertility (adjusted odds ratio [OR], 1.24; 95% CI, 1.10-1.64; P = .003). The absolute risk was 0.204 (95% CI, 0.092-0.391). For patients with OSA in the group without treatment, the adjusted OR was 1.80 (95% CI, 1.56-2.07; P < .001) for infertility compared with patients without OSA. Conclusions and Relevance: Results of this study support the hypothesis that OSA increases the risk of infertility in male patients, and the risk is associated with the OSA exposure time. Furthermore, no OSA management or treatment is associated with a higher infertility risk.