Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer.

BACKGROUND: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance. PATIENTS AND METHODS: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance. ctDNA isolated at multiple time points in the patient treatment course (before, on-treatment and at progression) was sequenced using a novel >750-gene intron/exon targeted sequencing panel. Where available, matched tumour biopsies were whole exome and RNA sequenced and also used to assess nuclear RAD51. RESULTS: BRCA1/2 reversion mutations were present in 60% of patients and were the most prevalent form of resistance. In 10 cases, reversions were detected in ctDNA before clinical progression. Two new reversion-based mechanisms were identified: (i) intragenic BRCA1/2 deletions with intronic breakpoints; and (ii) intragenic BRCA1/2 secondary mutations that formed novel splice acceptor sites, the latter being confirmed by in vitro minigene reporter assays. When seen before commencing subsequent treatment, reversions were associated with significantly shorter time to progression. Tumours with reversions retained HRD mutational signatures but had functional homologous recombination based on RAD51 status. Although less frequent than reversions, nonreversion mechanisms [loss-of-function (LoF) mutations in TP53BP1, RIF1 or PAXIP1] were evident in patients with acquired resistance and occasionally coexisted with reversions, challenging the notion that singular resistance mechanisms emerge in each patient. CONCLUSIONS: These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.

Self-Assembly of Delta-Formamidinium Lead Iodide Nanoparticles to Nanorods: Study of Memristor Properties and Resistive Switching Mechanism.

In the quest for advanced memristor technologies, this study introduces the synthesis of delta-formamidinium lead iodide (δ-FAPbI3) nanoparticles (NPs) and their self-assembly into nanorods (NRs). The formation of these NRs is facilitated by iodide vacancies, promoting the fusion of individual NPs at higher concentrations. Notably, these NRs exhibit robust stability under ambient conditions, a distinctive advantage attributed to the presence of capping ligands and a crystal lattice structured around face-sharing octahedra. When employed as the active layer in resistive random-access memory devices, these NRs demonstrate exceptional bipolar switching properties. A remarkable on/off ratio (105) is achieved, surpassing the performances of previously reported low-dimensional perovskite derivatives and α-FAPbI3 NP-based devices. This enhanced performance is attributed to the low off-state current owing to the reduced number of halide vacancies, intrinsic low dimensionality, and the parallel alignment of NRs on the FTO substrate. This study not only provides significant insights into the development of superior materials for memristor applications but also opens new avenues for exploring low-dimensional perovskite derivatives in advanced electronic devices.

Pegylated interferon plus optimized weight-based ribavirin dosing negate the influence of weight and body mass index on early viral kinetics and sustained virological response in chronic hepatitis C.

AIM: Elevated body mass index (BMI) in chronic hepatitis C (CHC) has been associated with reduced rates of sustained virological response (SVR). The aims of this study were to determine whether early viral kinetics (and subsequently SVR) are influenced by weight or BMI by measuring HCV RNA at week 4 using two PCR assays with differing sensitivities. METHODS: Patients with CHC treated with peginterferon plus weight-based ribavirin were included in this retrospective study. Body mass index, pretreatment viral load, genotype and liver histology were abstracted from the clinical database. HCV RNA PCR (lower limit of detection (LLD) <50 IU/mL) at treatment week 4 and 6 months after completion of therapy were recorded to determine the presence of rapid virological response (RVR-50) and SVR, respectively. In those who achieved RVR-50, stored week 4 serum was retested using Taqman (LLD < 15 IU/mL, RVR-15). RESULTS: Of 134 patients included (genotype 1 57%, BMI 26.7 ± 4.5 kg/m², ribavirin dose 13.9 ± 2.6 mg/kg/day), 59% achieved SVR. RVR-50 was observed in 39.6% and RVR-15 in 27.6%. Neither body weight nor BMI influenced RVR-50, RVR-15 or SVR. The positive predictive values (PPVs) of RVR-50 and RVR-15 for SVR were 88.7% and 97.3% (P = 0.23). RVR-50 and RVR-15 superceded genotype and viral load as the strongest independent predictors of SVR (OR 9.25 (1.9-45.11) and OR 30.74 (3.08-317.96), respectively). CONCLUSIONS: RVR is the strongest predictor of SVR. Early viral kinetics is not influenced by body weight or BMI when weight-based ribavirin is prescribed.

Holographic analysis of the initial canine displacement produced by four different retraction springs.

OBJECTIVES: To estimate and compare the magnitude and direction of initial displacement of the canine produced by four different canine retraction springs. MATERIALS AND METHODS: A freshly macerated mandible was used as an experimental model. First premolars were extracted, and strap-up was done with a 0.018 inch Roth Preadjusted Edgewise System (3M Unitek, Monrovia, Calif). The canine was subjected to loads of 4 oz, 5 oz, and 6 oz, each applied by four different canine retraction springs, that is, closed coil spring, open coil spring, PG spring, and T-loop retraction spring. The magnitude and direction of the initial displacement of the canine were studied by means of double-exposure interferometry. RESULTS: The PG spring produced the highest initial displacement for a given force among the force systems used, followed by open coil, closed coil, and T-loop. Maximum tipping was observed with the open coil spring, followed by the PG spring, the closed coil spring, and the T-spring. CONCLUSION: The T-loop may be preferred whenever minimal tipping is performed. The PG spring may be preferred over other springs whenever a higher magnitude of displacement is desired. Closed coil springs may be preferred whenever a reasonable magnitude of displacement is required and reasonable tipping is allowed.

Simultaneous co-delivery of neuroprotective drugs from multi-loaded PLGA microspheres for the treatment of glaucoma.

Glaucoma is a multifactorial neurodegenerative disorder and one of the leading causes of irreversible blindness globally and for which intraocular pressure is the only modifiable risk factor. Although neuroprotective therapies have been suggested to have therapeutic potential, drug delivery for the treatment of ocular disorders such as glaucoma remains an unmet clinical need, further complicated by poor patient compliance with topically applied treatments. In the present study we describe the development of multi-loaded PLGA-microspheres (MSs) incorporating three recognised neuroprotective agents (dexamethasone (DX), melatonin (MEL) and coenzyme Q10 (CoQ10)) in a single formulation (DMQ-MSs) to create a novel sustained-release intraocular drug delivery system (IODDS) for the treatment of glaucoma. MSs were spherical, with a mean particle size of 29.04 ±â€¯1.89 µm rendering them suitable for intravitreal injection using conventional 25G-32G needles. >62% incorporation efficiency was achieved for the three drug cargo and MSs were able to co-deliver the encapsulated active compounds in a sustained manner over 30-days with low burst release. In vitro studies showed DMQ-MSs to be neuroprotective in a glutamate-induced cytotoxicity model (IC50 10.00 ±â€¯0.94 mM versus 6.89 ±â€¯0.82 mM in absence of DMQ-MSs) in R28 cell line. In vivo efficacy studies were performed using a well-established rodent model of chronic ocular hypertension (OHT), comparing single intravitreal injections of microspheres of DMQ-MSs to their equivalent individual single-drug loaded MSs mixture (MSsmix), empty MSs, no-treatment OHT only and naïve groups. Twenty one days after OHT induction, DMQ-MSs showed a significantly neuroprotective effect on RGCs compared to OHT only controls. No such protective effect was observed in empty MSs and single-drug MSs treated groups. This work suggests that multi-loaded PLGA MSs present a novel therapeutic approach in the management of retinal neurodegeneration conditions such as glaucoma.

Analysis of tumour-immune evasion with chemo-immuno therapeutic treatment with quadratic optimal control.

A simple mathematical model for the growth of tumour with discrete time delay in the immune system is considered. The dynamical behaviour of our system by analysing the existence and stability of our system at various equilibria is discussed elaborately. We set up an optimal control problem relative to the model so as to minimize the number of tumour cells and the chemo-immunotherapeutic drug administration. Sensitivity analysis of tumour model reveals that parameter value has a major impact on the model dynamics. We numerically illustrate how does these delay can change the stability region of the immune-control equilibrium and display the different impacts to the control of tumour. Finally, epidemiological implications of our analytical findings are addressed critically.

Pyoderma gangrenosum: A clinico-epidemiological study.

BACKGROUND: Pyoderma gangrenosum is a neutrophilic dermatosis of unknown etiology, with inconstant systemic associations and a variable prognosis. AIMS: To study the clinical features and systemic associations of pyoderma gangrenosum and its response to treatment. METHODS: All patients diagnosed to have pyoderma gangrenosum at the dermatology department of the Government Medical College, Kozhikode, from January 01, 2005 to December 31, 2014 were included in this prospective study. RESULTS: During the 10-year study period, 61 patients were diagnosed to have pyoderma gangrenosum. A male predilection was noted. The most common clinical type was ulcerative pyoderma gangrenosum (90.2%). More than 60% of patients had lesions confined to the legs; 78.7% had a single lesion and 27.9% had systemic associations. Most patients required systemic steroids. Patients with disease resistant to steroid therapy were treated with intravenous immunoglobulin G and split-thickness skin grafts under immunosuppression induced by dexamethasone pulse therapy. All except one patient attained complete disease resolution. LIMITATIONS: The main limitation of our study was the small sample size. CONCLUSIONS: The male predilection documented by us was contrary to most previous studies. We found split-thickness skin graft to be a useful option in resistant cases. More prospective studies may enable the formulation of better diagnostic criteria for pyoderma gangrenosum and improve its management.

Diabetes mellitus, insulin resistance, and metabolic syndrome in HIV-positive patients in South India.

Insulin resistance, diabetes mellitus, and metabolic syndrome in patients with human immunodeficiency virus (HIV) infection are increasingly being reported in the global medical literature. This cross-sectional study was done to describe the occurrence of metabolic syndrome, diabetes mellitus, and insulin resistance in HIV-positive patients in a tertiary referral center in South India. A total of 60 patients who had HIV infection for 12 months or more were enrolled in the study. Of these, 30 patients were antiretroviral therapy (ART)-naïve, and 30 were treated with ART. Biochemical estimations (fasting blood glucose, 75 g oral glucose tolerance test, lipid profile, and fasting insulin) and anthropometric measurements (height, weight, and waist circumference) were performed for each patient. Metabolic syndrome was diagnosed using National Cholesterol Education Program-Adult Treatment Plan III criteria, and insulin resistance was calculated applying the homeostasis model assessment method. Diabetes mellitus, impaired fasting glycemia, and impaired glucose tolerance were diagnosed based on American Diabetes Association criteria. A high prevalence of metabolic syndrome was observed in patients with HIV (16/60), and was more prevalent in the ART-treated group (13/30; P = 0.028). Similarly, insulin resistance was also noted to be high (24/60), and of these patients, 15 were on ART. Seventy-five percent of patients with metabolic syndrome had insulin resistance. Diabetes was diagnosed in one patient who was ART-naïve and in six patients who were on ART. Our observations suggest an increased prevalence of metabolic syndrome, insulin resistance, and diabetes mellitus in ART-treated patients. These warrant attention and substantiation with larger studies. While ART improves survival, it may lead on to cardiovascular morbidity and mortality, especially in the Indian subcontinent where there is a genetic predisposition to cardiovascular risk.