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The results obtained are expected to contribute to a more complete understanding of the hemodynamic changes resulting from pregnancy.

Trastuzumab (Herceptin) is the key systemic therapy for HER2-positive breast cancer. However, the initial response rate is limited to approximately 50% in patients. Moreover, most patients, especially at an advanced stage, eventually develop acquired resistance. Understanding the mechanisms of trastuzumab resistance is crucial for achieving better treatment outcome in this group of patients.

A trastuzumab-resistant (TR) cell line was developed using the BT474 HER2-positive breast cancer cell line. Whole-transcriptome expression array was performed and the TR-related gene NDUFA4L2 was identified by differential expression analysis between BT474 and BT474-TR. Mitochondrial localization of NDUFA4L2 was confirmed by immunofluorescence and western blotting using mitochondrial fractionation. Mitochondrial function and energy metabolism were evaluated using Seahorse, ATP production, and lactate production assays, and cellular reactive oxygen species (ROS) levels were determined using DCFDA. NDUFA4L2 expression in patients was evaluated by immunohistochemistry, and relapse-free survival was analyzed using the Kaplan-Meier method.

NDUFA4L2 was highly expressed in the TR HER2-positive breast cancer cell line. High expression level of NDUFA4L2 was associated with shorter relapse-free intervals in trastuzumab-treated HER2-positive breast cancer patients. Overexpression of NDUFA4L2 enhanced Warburg effects, enhanced aerobic glycolysis, reduced oxygen consumption, and lowered ROS production. Mechanistically, overexpression of NDUFA4L2 facilitated mitochondrial relocalization of HER2 and suppressed ROS production, thus rendering cancer cells more resistant to trastuzumab treatment.

We identified NDUFA4L2 as a new biomarker and potential therapeutic target for TR HER2-positive breast cancer.

We identified NDUFA4L2 as a new biomarker and potential therapeutic target for TR HER2-positive breast cancer.Atherosclerosis is a chronic inflammatory disease. Several circulating inflammatory markers have been proposed for clinical use due to their ability to predict future cardiovascular events and may be useful for identifying people at high risk who might benefit from specific treatment to reduce this risk. Moreover, the identification of new therapeutic targets will allow the development of drugs that can help reduce the high residual risk of recurrence of cardiovascular events in patients with coronary artery disease. The clinical benefits of reducing recurrent major cardiovascular events recently shown by canakinumab and colchicine have renewed the cardiology community's interest in inflammation as an aetiopathogenic mechanism for atherosclerosis. This review explores the use of C-reactive protein, which is the most frequently studied biomarker in this context; the concept of residual risk in primary and secondary cardiovascular prevention; and the current recommendations in international guidelines regarding the role of this inflammatory biomarker in cardiovascular risk stratification.Coronary vasomotion disorders represent a frequent cause of angina and/or dyspnoea in patients with non-obstructed coronary arteries. The highly sophisticated interplay of vasodilatation and vasoconstriction can be assessed in an interventional diagnostic procedure. Established parameters characterising adequate vasodilatation are coronary blood flow at rest, and, after drug-induced vasodilation, coronary flow reserve, and microvascular resistance (hyperaemic microvascular resistance, index of microcirculatory resistance). Tivantinib An increased vasoconstrictive potential is diagnosed by provocation testing with acetylcholine or ergonovine. This enables a diagnosis of coronary epicardial and/or microvascular spasm. Ischaemia associated with microvascular spasm can be confirmed by ischaemic ECG changes and the measurement of lactate concentrations in the coronary sinus. Although interventional diagnostic procedures are helpful for determining the mechanism of the angina, which may be the key to successful medical treatment, they are still neither widely accepted nor applied in many medical centres. This article summarises currently well-established invasive methods for the diagnosis of coronary functional disorders causing angina pectoris.

Urinalysis is used as a first-line investigation throughout healthcare to indicate bacteriuria and guide treatment of potential urinary tract infections. In light of rising bacterial multi-resistance, we aim to analyse its diagnostic accuracy, determine its usefulness in a present-day setting and evaluate current antibiotic resistance patterns across a Trust population.

A retrospective case series of 712 paired urinalysis and urine culture results was obtained over a 1-month period. Sensitivity, specificity and diagnostic accuracy were calculated, and resistance profiles of commonly used Trust antibiotics assessed using statistical analysis.

A high false negative rate of nitrites on urinalysis, with sensitivity of 38.4%, was found. Leucocyte sensitivity was 87.6% and specificity 39.7%, with no improvement in diagnostic accuracy seen when combining both. Positive urine culture growth demonstrated a substantial resistance pattern to trimethoprim of 48%, compounded by a statistically significant correlatiog this growing concern in modern-day healthcare.

5-fluorouracil (5-FU) and mitomycin-C (MMC) with radiotherapy (RT) remain an established treatment for patients with anal cancer (AC). Genetic mutations in two major metabolizing enzymes for 5-FU; dihydropyrimidine dehydrogenase (

and thymidylate synthetase (

), have been associated with clinical response and toxicity. However, their place in the treatment of AC remains undetermined.

We retrospectively reviewed 21 patients with AC, including T2-4, N0-1, M0 or T1-4, N2-3, and M0 treated between 2012 and 2018. All patients were treated with 5-FU 1,000 mg/m

/day via continuous intravenous (IV) infusion 1-4 and 29-32, MMC 10 mg/m

IV bolus days 1 and 29 plus RT. Patients who developed ⩾3 grade toxicities were tested for the

and

genes. Treatment was either modified with reduced doses or changed to MMC 10 mg/m

day 1 and 29 with cisplatin 25 mg/m

/week plus RT. Toxicities and responses were collected.

Six out of 21 patients who developed ⩾3 grade toxicities including pancytopenia, neutropenia, thrombocytopenia, mucositis, nausea, rash, and nephritis were found to have genetic mutations

2RG/3RC (

 = 2), 3RG/3RC (

 = 1), 2R/2R (

 = 2), T

3'UTR del/Ins (

 = 2), and

c.