Background
Breast cancer is the most common cancer type that affects women. In hormone receptor–positive (HR+), human epidermal growth factor receptor 2−negative (HER2–) advanced breast cancer (ABC), ...phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (
PIK3CA)
is the most frequently mutated gene associated with poor prognosis. This study evaluated the frequency of
PIK3CA
mutations in the Taiwanese breast cancer population.
Methodology
This is a retrospective study; patient data were collected for 2 years from a next-generation sequencing database linked to electronic health records (EHRs). The primary endpoint was the regional prevalence of
PIK3CA
mutation. The secondary endpoints were to decipher the mutation types across breast cancer subtype, menopausal status, and time to treatment failure after everolimus (an mTOR inhibitor) or cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment.
Results
PIK3CA
mutations were identified in 278 of 728 patients (38%).
PIK3CA
mutations were reported in 43% of patients with HR−/HER2+ subtype and 42% of patients with HR+/HER2– postmenopausal status. A lower prevalence of
PIK3CA
mutations was observed in triple-negative (27%) and HR+/HER2– premenopausal patients (29%). The most common mutation was at exon 20 (H1047R mutation, 41.6%), followed by exon 9 (E545K mutation, 18.9% and E542K mutation, 10.3%). Among patients treated with CDK4/6 inhibitors, the median time to treatment failure was 12 months (95% CI: 7-21 months) in the
PIK3CA
mutation cohort and 16 months (95% CI: 11-23 months) in the
PIK3CA
wild-type cohort, whereas patients receiving an mTOR inhibitor reported a median time to treatment failure of 20.5 months (95% CI: 8-33 months) in the
PIK3CA
mutation cohort and 6 months (95% CI: 2-9 months) in the
PIK3CA
wild-type cohort.
Conclusion
A high frequency of
PIK3CA
mutations was detected in Taiwanese patients with breast cancer, which was consistent with previous studies. Early detection of
PIK3CA
mutations might influence therapeutic decisions, leading to better treatment outcomes.
SALL1 is a multi-zinc finger transcription factor that regulates organogenesis and stem cell development, but the role of SALL1 in tumor biology and tumorigenesis remains largely unknown.
We analyzed ...SALL1 expression levels in human and murine breast cancer cells as well as cancer tissues from different types of breast cancer patients. Using both in vitro co-culture system and in vivo breast tumor models, we investigated how SALL1 expression in breast cancer cells affects tumor cell growth and proliferation, metastasis, and cell fate. Using the gain-of function and loss-of-function strategies, we dissected the molecular mechanism responsible for SALL1 tumor suppressor functions.
We demonstrated that SALL1 functions as a tumor suppressor in breast cancer, which is significantly down-regulated in the basal like breast cancer and in estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2) triple negative breast cancer patients. SALL1 expression in human and murine breast cancer cells inhibited cancer cell growth and proliferation, metastasis, and promoted cell cycle arrest. Knockdown of SALL1 in breast cancer cells promoted cancer cell growth, proliferation, and colony formation. Our studies revealed that tumor suppression was mediated by recruitment of the Nucleosome Remodeling and Deacetylase (NuRD) complex by SALL1, which promoted cancer cell senescence. We further demonstrated that the mechanism of inhibition of breast cancer cell growth and invasion by SALL1-NuRD depends on the p38 MAPK, ERK1/2, and mTOR signaling pathways.
Our studies indicate that the developmental control gene SALL1 plays a critical role in tumor suppression by recruiting the NuRD complex and thereby inducing cell senescence in breast cancer cells.
Mammographic breast density (MBD) is decreased by tamoxifen, but the effect of aromatase inhibitors is less clear.
We enrolled early-stage postmenopausal patients with breast cancer initiating ...adjuvant aromatase inhibitor therapy and ascertained mammograms before and at an average 10 months of aromatase inhibitor therapy. We matched cases to healthy postmenopausal women (controls) from a large mammography screening cohort on age, baseline body mass index, baseline MBD, and interval between mammograms. We estimated change in MBD using a computer-assisted thresholding program (Cumulus) and compared differences between cases and matched controls.
In predominantly White women (96%), we found 14% of the 387 eligible cases had a MBD reduction of at least 5% after an average of 10 months of aromatase inhibitor therapy. MBD reductions were associated with higher baseline MBD, aromatase inhibitor use for more than 12 months, and prior postmenopausal hormone use. Comparing each case with her matched control, there was no evidence of an association of change in MBD with aromatase inhibitor therapy median case-control difference among 369 pairs was -0.1% (10th and 90th percentile: -5.9%, 5.2%) P = 0.51. Case-control differences were similar by type of aromatase inhibitor (P's 0.41 and 0.56); prior use of postmenopausal hormones (P = 0.85); baseline MBD (P = 0.55); and length of aromatase inhibitor therapy (P = 0.08).
In postmenopausal women treated with aromatase inhibitors, 14% of cases had a MBD reduction of more than 5%, but these decreases did not differ from matched controls. These data suggest that MBD is not a clinically useful biomarker for predicting the value of aromatase inhibitor therapy in White postmenopausal women.
•Seeds were treated after equilibration to aw 0.75 and soaking.•HPCD reduced fungi and bacteria on oats, and barley grains, soy and mung beans.•Salmonella was more resistant than Escherichia ...coli.•HPCD prevented growth of A. niger and P. roqueforti for 10 d after treatment.•More than 90% of mung beans germinated after treatment.
Display omitted
Decontamination of low aw foods without impairing the food quality is challenging, particularly for sprouting seeds. This study aimed to explore the lethality of high pressure carbon dioxide (HPCD) to Salmonella enterica, E. coli AW1.7, A. niger, P. roquforti, and Fusarium on beans, cereal grains, and ground pepper. The optimal antimicrobial effect of HPCD was achieved by equilibration of the aw to 0.75, followed by soaking in water and treatments with water-saturated CO2. HPCD reduced the viable cell counts of E. coli and Salmonella by 3–10 log(CFU/g), and prevented fungal growth during 10 d of incubation. More than 90% of mung beans germinated but the germination of oats was impaired after fungicidal or bactericidal treatments with HPCD. Overall, HPCD can be a promising antimicrobial treatment but treatment parameters need to be optimized for each type of seed.
Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of pre-leukemic cells that acquire specific mutations. Although individuals with CH are healthy, they ...are at an increased risk of developing myeloid malignancies, suggesting that additional alterations are needed for the transition from a pre-leukemia stage to frank leukemia. To identify signaling states that cooperate with pre-leukemic cells, we used an in vivo RNAi screening approach. One of the most prominent genes identified was the ubiquitin ligase TRAF6. Loss of TRAF6 in pre-leukemic cells results in overt myeloid leukemia and is associated with MYC-dependent stem cell signatures. TRAF6 is repressed in a subset of patients with myeloid malignancies, suggesting that subversion of TRAF6 signaling can lead to acute leukemia. Mechanistically, TRAF6 ubiquitinates MYC, an event that does not affect its protein stability but rather represses its functional activity by antagonizing an acetylation modification.
Display omitted
•Loss of TRAF6 results in progression of clonal hematopoiesis to AML/MPN•Loss of TRAF6 results in increased MYC activation•TRAF6 ubiquitinates MYC and represses its transcriptional activity•TLR-induced TRAF6 activation suppresses MYC function in AML
Individuals with clonal hematopoiesis have an increased risk of developing hematopoietic malignancies. Starczynowski and colleagues demonstrate that loss of TRAF6 signaling contributes to the development of AML/MPN in the context of clonal hematopoiesis by activating MYC. TRAF6 functions as a tumor suppressor by ubiquitinating MYC and repressing its transcriptional activity.
Concordant activation of MYC and BCL-2 oncoproteins in double-hit lymphoma (DHL) results in aggressive disease that is refractory to treatment. By integrating activity-based proteomic profiling and ...drug screens, polo-like kinase-1 (PLK1) was identified as an essential regulator of the MYC-dependent kinome in DHL. Notably, PLK1 was expressed at high levels in DHL, correlated with MYC expression, and connoted poor outcome. Further, PLK1 signaling augmented MYC protein stability, and in turn, MYC directly induced PLK1 transcription, establishing a feed-forward MYC-PLK1 circuit in DHL. Finally, inhibition of PLK1 triggered degradation of MYC and of the antiapoptotic protein MCL-1, and PLK1 inhibitors showed synergy with BCL-2 antagonists in blocking DHL cell growth, survival, and tumorigenicity, supporting clinical targeting of PLK1 in DHL.
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduce blood pressure without compensatory heart rate elevation, possibly by modulating sympathetic/parasympathetic activity. This may contribute to ...their cardiovascular benefits in type 2 diabetes (T2D). We evaluated the effects of dapagliflozin (DAPA) on measures of cardiovascular autonomic neuropathy (CAN), cardiac function, and glucose variability (GV) in T2D.
Pilot, randomized, two-period crossover trial comparing 12-week DAPA versus 12-week glimepiride treatment on CAN measures (cardiovascular autonomic reflex tests and heart rate variability), B-type natriuretic peptide (BNP), and GV (Abbott's Libre Pro devices) using signed rank tests and mixed models from baseline to 12 weeks within and between each period.
Forty-five T2D participants on metformin monotherapy (mean age 57 ± 8 years, duration 7 ± 6 years, HbA1c 7.8 ± 1.3%) were enrolled with 41 completing the trial. There were no differences in CAN indices or BNP with each drug compared to baseline and each other. Participants on DAPA demonstrated greater weight loss, reduced time in hypoglycemia, and improved GV compared to glimepiride.
Short term treatment with DAPA did not affect CAN measures or BNP in uncomplicated and relatively healthy T2D participants. Longer prospective studies in patients with advanced disease are needed to better understand relationships between SGLT-2 inhibitors and CAN.
Clinical trial registration: NCT02973477
•No effect of 12-week dapagliflozin on cardiovascular autonomic neuropathy measures•Dapagliflozin was significantly associated with lower glucose variability.•Participants on dapagliflozin had greater weight loss compared to glimepiride.
ObjectiveThis study aims to explore health beliefs toward lung cancer screening with low dose computed tomography among Chinese American high-risk smokers. MethodsGuided by the Health Belief Model, ...semi-structured individual interviews were conducted with Chinese American high-risk smokers via phone. Additional questionnaires on demographic information, history of smoking and lung cancer screening were collected via email or phone before the interview, depending on participants' preference. Content analysis was used to extract meaningful and significant themes in the dataset. Constant comparison analysis and process coding were used to categorize and code data. ResultsData saturation was reached after interviewing 12 participants. Chinese American high-risk smokers perceived a low susceptibility to lung cancer, since they believed various protective factors of lung cancer (e.g., doing exercise, healthy diet, etc.) reduced their risk of getting lung cancer. All the participants perceived a high severity of lung cancer. They acknowledged lung cancer would have a huge impact on their life. Perceived benefits of lung cancer screening were accurate in most aspects although minor confusions were still noticed among this population. Perceived barriers varied on participants', physicians', and institutional levels. High-risk Chinese American smokers had little confidence to screening for lung cancer. Cues to action for them to screening for lung cancer included recommendations from health care providers, support from family members and friends, and information shared on Chinese-based social media. ConclusionsMisconceptions and barriers to screening for lung cancer existed widely among Chinese American high-risk smokers. Intervention programs and targeted health education should be implemented to promote lung cancer screening among this population.
PDF
