PI3K inhibitors in trastuzumab-resistant HER2-positive breast cancer cells with PI3K pathway alterations

The activation of the PI3K signaling pathway resulting from genetic alterations induces carcinogenesis and resistance to anticancer therapies. Breast cancer is a major malignancy that is associated with dysregulation of the PI3K signaling pathway. PIK3CA mutations and PTEN loss occur in every subtype of breast cancer. PI3K inhibitors are being evaluated in breast cancer after the success of an alpha isoform-specific PI3K inhibitor in estrogen receptor (ER)-positive/HER2-negative metastatic breast cancer. Some preclinical data indicate the potential for PI3K/mTOR targeting in combination with trastuzumab for HER2-positive breast cancer with or without expression of the estrogen receptor. However, the role of this therapy in HER2-positive breast cancer with PIK3CA mutations and/or PTEN loss remains unclear. We examined three HER2-positive, ER-negative breast cancer cell lines to determine the efficacy of a novel alpha isoform-specific PI3K inhibitor in combination with trastuzumab. The results indicated that this combination was effective in PIK3CA-mutant or PTEN-deficient breast cancer cells by inducing apoptosis and inhibiting the expression of downstream proteins. PTEN loss by siRNA modulation in parental HER2-positive cancer cells with PI3K signaling pathway alterations could not confer resistance to alpelisib or GDC-0077 plus trastuzumab. We selected the CK-MB-1 cell line without alterations in the PI3K pathway to demonstrate that PI3K inhibitors plus trastuzumab represented a biomarker-specific treatment. In vivo effects of alpelisib plus trastuzumab were tested and confirmed in a mouse model, showing the combination strategy offered the best opportunity to achieve tumor volume reduction. With known safety profiles, this cytotoxic chemotherapy-free regimen warrants further attention as a biomarker-driven strategy for treating HER2-positive breast cancer.     

Cardiovascular Medication Use and Risk of Acute Exacerbation in Patients With Asthma-COPD Overlap (CVACO Study)

PurposeCurrent clinical guidelines are unclear regarding the association of cardiovascular medication with the risk of acute exacerbation (AE) in patients with asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO).MethodsWe conducted a retrospective cohort study by interrogating the claims database of Taipei Veterans General Hospital. Patients with coexistent fixed airflow limitation and asthma were enrolled as an ACO cohort between 2009 and 2017. Exposure to cardiovascular medications, including angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), non-selective beta-blockers, cardioselective beta-blockers, dihydropyridine (DHP) calcium channel blockers (CCBs), and non-DHP CCBs, in 3-month period each served as time-dependent covariates. Patients receiving a cardiovascular medication ≥ 28 cumulative daily doses were defined as respective cardiovascular medication users. Patients were followed up until December 31, 2018. The primary endpoint was severe AE, defined as hospitalization or emergency department visit for either asthma, COPD, or respiratory failure. The secondary outcome was moderate AE.ResultsThe final study cohort consisted of 582 ACO subjects, with a mean follow-up period of 2.98 years. After adjustment, ARB (hazard ratio [HR], 0.64, 95% confidence interval [CI], 0.44–0.93, P = 0.019), cardioselective beta-blocker (HR, 0.29, 95% CI, 0.11–0.72, P = 0.008) and DHP CCB (HR, 0.66, 95% CI, 0.45–0.97, P = 0.035) therapies were associated with lower risks of severe AE. ARB (HR, 0.42, 95% CI, 0.30–0.62, P < 0.001) and DHP CCB (HR, 0.55, 95% CI, 0.38–0.80, P = 0.002) therapies were associated with lower risks of moderate AE. Cardioselective beta-blockers, ARBs, and DHP CCBs were associated with lower risks of severe AE in frequent exacerbators. ACEI, non-selective beta-blocker, or non-DHP CCB use did not change the risk of severe AE.ConclusionsARB, cardioselective beta-blocker, and DHP CCB therapies may lower the risk of AE in patients with ACO.     

Neonatal clavicular fracture: clinical analysis of incidence, predisposing factors, diagnosis, and outcome

The objective of this study is to identify maternal, perinatal, and fetal risk factors for clavicular fracture in a single institution. We performed a prospective study of all deliveries during a 14-month period to identify confirmed cases of neonatal clavicular fracture. The control group consisted of the deliveries immediately preceding and following the index cases. Fifty-three cases of clavicular fracture were identified among the 4789 deliveries from October 1995 through November 1996 for an incidence of 1.11%. Three neonates in the clavicular fracture group were delivered through cesarean section. Neonates with fracture were significantly heavier at birth than those without (3564 vs. 3283 g, p <0.001), and had a lower mean head-to-abdominal circumference ratio (0.93 vs. 1.08, p <0.001), history of giving birth to a macrosomia (21 vs. 4%, p <0.05). The anterior shoulder was the predominant site of fracture (30/53). Fracture was detected mostly during the first 3 days of neonatal life (46/53). The outcome was benign, with complete recovery in all cases and no associated neurological sequelae. Neonatal clavicular fracture tended to be associated with neonatal somatometric characteristics and difficult deliveries. Considering the benign nature of this birth trauma, more invasive intrapartum management to lower its incidence is not advised.     

One-year efficacy of tenofovir alafenamide in patients with chronic hepatitis B: An observational study

Non-inferior antiviral efficacy and better renal safety have been reported in chronic hepatitis B patients with tenofovir alafenamide (TAF) treatment. The experience in real-world clinical practice is limited.We aimed to explore the efficacy after 1-year TAF treatment.A total of 148 patients (42 HBeAg-positive and 106 HBeAg-negative) with TAF treatment ≥1 year were included. Virological suppression (<20 IU/mL or undetectable), HBsAg level, alanine aminotransferase (ALT) normalization (≤36 U/L), and estimated glomerular filtration rate (eGFR) were analyzed at 1 year. Multivariate logistic regression analysis was performed to determine the associated factors for virological suppression and ALT normalization.Virological suppression was achieved in 83% and the 1-year median decline of hepatitis B virus DNA was 5.18 log IU/mL. ALT normalization occurred in 75.7%. HBsAg level decreased at a median of 0.27 log IU/mL with significant difference from baseline (P < .001). Baseline ALT (odds ratio [OR] 1.005, 95% confidence interval [CI] 1.000–1.010, P = .036) and hepatitis B virus DNA (OR 0.222, 95% CI 0.079–0.621, P = .004) were significant factors for 1-year virological suppression. Age (OR 1.064, 95% CI 1.003–1.130, P = .041) was associated with ALT normalization. Significant changes were observed in creatinine (mean increase 0.03 mg/dL, P = .011) and eGFR (mean decrease 2.6 mL/min/1.73 m², P = .004) after 1-year TAF treatment.One-year TAF treatment came to good virological response, modest ALT normalization rate and significant HBsAg decline. The observation of significant changes in eGFR warranted further studies.     

Characteristics and immune checkpoint inhibitor effects on non-smoking non-small cell lung cancer with KRAS mutation: A single center cohort (STROBE-compliant)

Kirsten rat sarcoma (KRAS) mutation (KRASm) is associated with poor prognosis in non-small cell lung cancer (NSCLC) patients. We have aimed to survey NSCLC patients harboring KRASm in Taiwan, where never-smoking lung adenocarcinoma predominates, and analyze the immune checkpoint inhibitor effect on NSCLC harboring KRASm.NSCLC patients with KRASm were enrolled and tested on programmed death-ligand 1 (PD-L1) expression using available tissue. We analyzed their clinical features, PD-L1 status, responses to ICIs, and overall survival (OS).We studied 93 patients with a median age 66.0 years, 23.7% of whom were women, and 22.6% were never-smokers. The results showed that G12C (36.6%) was the most common KRASm. In 47 patients with available tissue for PD-L1 testing, PD-L1 expression was positive in 66.0% of patients, while PD-L1 ≥50% was higher in ever-smokers (P = .038). Among 23 patients receiving ICI treatment, those with PD-L1 ≥50% experience a 45.5% response rate to ICI. There were benefits from ICI treatment on OS compared with no ICI treatment (median OS 35.6 vs 9.8 months, P = .002) for all of our patients, and for patients with PD-L1 ≥50% (median OS not-reached vs 8.4 months, P = .008). There were no differences in survival across different KRAS subtypes (P = .666).Never-smokers composed more than one-fifth of KRASm in NSCLC in Taiwan. A high PD-L1 expression was related to smoking history and responded well to ICI. ICI treatment improved the OS in NSCLC patients with KRASm, particularly those with PD-L1 ≥50%.     

Correction: Discovery of 8-prenylnaringenin from hop (Humulus lupulus L.) as a potent monoacylglycerol lipase inhibitor for treatments of neuroinflammation and Alzheimer’s disease

Correction for ‘Discovery of 8-prenylnaringenin from hop (Humulus lupulus L.) as a potent monoacylglycerol lipase inhibitor for treatments of neuroinflammation and Alzheimer’s disease’ by Min-Che Tung et al., RSC Adv., 2021, 11, 31062–31072, https://doi.org/10.1039/D1RA05311F.

The authors regret that the name of one of the authors (Hsing-Mien Hsu) was shown incorrectly in the original article. The corrected author list is as shown above.The authors also regret an incorrect version of Fig. 7 was included in the original article. The correct version of Fig. 7 is presented below.Open in a separate windowFig. 7The dose-dependent inhibitions of the identified inhibitors against hMAGL.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Hepatitis D virus infection in children with acute or chronic hepatitis B virus infection in Taiwan

To investigate the prevalence and clinical features of hepatitis D virus infection (HDV) in childhood, total antibody to hepatitis D antigen (anti-HD) in serum samples from 247 children (29 with acute hepatitis B, 68 with chronic hepatitis B, and 150 with asymptomatic hepatitis B surface antigen (HBsAg) carriers with normal liver function profiles) were studied using solid-phase competitive radioimmunoassay. Anti-HD was detected in three of the 29 children with acute hepatitis B and in only one of the 68 with chronic hepatitis B; none of the serum specimens from 150 asymptomatic carriers with normal liver function profile showed detectable anti-HD. All three children with HDV coinfection cleared HBsAg and seroconverted to anti-HBs, whereas one with superinfection finally had normal liver function without clearance of HBsAg. To identify possible sources of HDV infection, HBV markers and anti-HD in family members were also examined. One 4-month-old infant boy became infected through a blood transfusion from his hepatitis B e antigen (HBeAg)-positive carrier father, who had anti-HD. A 4-month-old infant girl was infected through close contact with her HBeAg-negative carrier father, who had HDV superinfection. The infection sources remained undefined in another two patients. The mothers of these four children were seronegative for anti-HD, indicating that perinatal transmission is not the usual mode of HDV infection in Taiwan. The natural course of either acute or chronic HBV infections in childhood in Taiwan may be more closely related to HBV itself, or to some other yet unrecognized factor, rather than to HDV infection.     

Laparoscopic-assisted vaginal hysterectomy with in situ morcellation for large uteri

STUDY OBJECTIVE: To estimate whether laparoscopic in situ morcellation (LISM) can facilitate laparoscopic-assisted vaginal hysterectomy (LAVH) for large uteri. DESIGN: Prospective study (Canadian Task Force classification II-1). SETTING: University-affiliated hospital. PATIENTS: In all, 147 women with myoma or adenomyosis weighing more than 500 g from January 2004 through December 2007 were enrolled. The patients were divided into 4 subgroups: patients with uteri weighing 500 to 749 g who had traditional LAVH without LISM (group 1A, n = 69) or with LISM (group 1B, n = 16); and patients with uteri weighing 750 g or more who were treated by traditional LAVH without LISM (group 2A, n = 38) or with LISM (group 2B, n = 24). INTERVENTIONS: Laparoscopic-assisted vaginal hysterectomy with or without LISM. MEASUREMENT AND MAIN RESULTS: No significant differences existed in age, body mass index, preoperative diagnoses, complications, or duration of hospital stay among groups. The mean uterine weights were 608 +/- 75, 597 +/- 66, 989 +/- 179, and 935 +/- 226 g for groups 1A, 1B, 2A, and 2B, respectively. The operative time (120 +/- 16 vs 157 +/- 36 minutes, p <.001; 140 +/- 19 vs 224 +/- 57 minutes, p <.001) were significantly shorter in patients with LISM than without in both groups 1 and 2. The estimated blood loss was highest in group 2A. Six (16%) patients lost more than 500 mL of blood and 3 (8%) of them needed blood transfusions. Conversion to laparotomy occurred in 1 (2.6%) of 38 patients in group 2A. No repeated surgery or surgical mortality occurred. CONCLUSION: Laparoscopic-assisted vaginal hysterectomy with LISM was an efficient and safe procedure for removal of large uteri during LAVH.