DNA polymerase B deficiency is linked to aggressive breast cancer: a comprehensive analysis of gene copy number, mRNA and protein expression in multiple cohorts

Short arm of chromosome 8 is a hot spot for chromosomal breaks, losses and amplifications in breast cancer. Although such genetic changes may have phenotypic consequences, the identity of candidate gene(s) remains to be clearly defined. Pol β gene is localized to chromosome 8p12 - p11 and encodes a key DNA base excision repair protein. Pol β may be a tumour suppressor and involved in breast cancer pathogenesis. We conducted the first and the largest study to comprehensively evaluate pol β in breast cancer. We investigated pol β gene copy number changes in two cohorts (n=128 & n=1952), pol β mRNA expression in two cohorts (n=249 & n=1952) and pol β protein expression in two cohorts (n=1406 & n=252). Artificial neural network analysis for pol β interacting genes was performed in 249 tumours. For mechanistic insights, pol β gene copy number changes, mRNA and protein levels were investigated together in 1 28 tumours and validated in 1952 tumours. Low pol β mRNA expression as well as low pol β protein expression was associated high grade, lymph node positivity, pleomorphism, triple negative, basal - like phenotypes and poor survival (ps<0.001). In oestrogen receptor (ER) positive sub - group that received tamoxifen, low pol β protein remains associated with aggressive phenotype and poor survival (ps<0.001). Artificial neural network analysis revealed ER as a top pol β interacting gene. Mechanistically, there was strong positive correlation between pol β gene copy number changes and pol β mRNA expression (p<0.0000001) and between pol β mRNA and pol β protein expression (p<0.0000001). This is the first study to provide evidence that pol β deficiency is linked to aggressive breast cancer and may have prognostic and predictive significance in patients

Single-strand selective monofunctional uracil-DNA glycosylase (SMUG1) deficiency is linked to aggressive breast cancer and predicts response to adjuvant therapy

Uracil in DNA is an important cause of mutagenesis. SMUG1 is a uracil DNA glycosylase that removes uracil through base excision repair. SMUG1 also processes radiation induced oxidative base damage as well as 5-fluorouracil incorporated into DNA during chemotherapy. We investigated SMUG1 mRNA expression in 249 primary breast cancers. SMUG1 protein expression was investigated in 1165 breast tumours randomised into two cohorts [training set (n=583) and test set (n=582)]. SMUG1 and chemotherapy response was also investigated in a series of 315 ER negative tumours (n=315). For mechanistic insights, SMUG1 was correlated to biomarkers of aggressive phenotype, DNA repair, cell cycle and apoptosis. Low SMUG1 mRNA expression was associated with adverse disease specific survival (p=0.008) and disease free survival (p=0.008). Low SMUG1 protein expression (25%) was associated with high histological grade (p<0.0001), high mitotic index (p<0.0001), pleomorphism (p<0.0001), glandular de-differentiation (p=0.0001), absence of hormonal receptors (ER-/PgR-/AR) (p<0.0001), presence of basal-like (p<0.0001) and triple negative phenotypes (p<0.0001). Low SMUG1 protein expression was associated with loss of BRCA1 (p<0.0001), ATM (p<0.0001) and XRCC1 (p<0.0001). Low p27 (p<0.0001), low p21 (p=0.023), mutant p53 (p=0.037), low MDM2 (p<0.0001), low MDM4 (p=0.004), low Bcl-2 (p=0.001), low Bax (p=0.003) and high MIB1 (p<0.0001) were likely in low SMUG1 tumours. Low SMUG1 protein expression was associated with poor prognosis in univariate (p<0.001) and multivariate analysis (p<0.01). In ER+ cohort that received adjuvant endocrine therapy, low SMUG1 protein expression remains associated with poor survival (p<0.01). In ER- cohort that received adjuvant chemotherapy, low SMUG1 protein expression is associated with improved survival (p=0.043). Our study suggests that low SMUG1 expression may correlate to adverse clinicopathological features and predict response to adjuvant therapy in breast cancer

Relation of endometrial thickness and pregnancy rates in intrauterine insemination following ovulation induction

Background: Controlled ovarian hyper stimulation (COH) using different agents with intrauterine insemination (IUI) are known treatment for infertility. Endometrial thickness (ET) is one of the predicting factors for clinical pregnancy along with other parameters. Many studies have been done in the past to find factors affecting the growth and maturity of the endometrium in women in IUI, but indigenous Indian studies regarding its relation with pregnancy were either limited or the results were unclear.Methods: A Prospective observational study was undertaken for assessing effects of clomiphene citrate (CC) and human menopausal gonadotropin (hMG) stimulated cycles on the ET and clinical pregnancy in single IUI cycle. Infertility cases were studied in two groups; Group A [ovulation induction (OI) with CC and IUI; n=101] and Group B (OI with hMG and IUI; n=103) after randomization using random number table as per standard protocol.Results: Comparable data obtained in mean age, duration of infertility, female and male factors in both groups. Mean ET on day of IUI in Group A and B was 8.35+2.08mm and 10.87+2.54mm respectively (p value <0.001). Range of ET in clinical pregnancies in Group A (n= 15) were 8.0- 12.9mm and 9.0- 12.9mm in Group B (n= 26). Ongoing pregnancies beyond 1st trimester were higher in Group B (n= 25) than Group A (n= 14).Conclusions: Mean ET and clinical pregnancy rate both were higher in hMG group compared to CC. This study identified an ‘optimum endometrial thickness’ (9.0-12.9mm) for achieving clinical pregnancy in hMG group

Functional outcome of mild and moderate residual varus in posterior stabilized total knee arthroplasty in primary osteoarthritis knee: a prospective study

Background: Total knee arthroplasty (TKA) is one of the most commonly done orthopaedic surgical procedures for treating severe arthritis of the knee joint caused by osteoarthritis or inflammatory arthritis. The current clinical investigation, done at the Sanjay Gandhi Institute of Trauma and Orthopaedics in Bengaluru, provided the short-term functional result of mild and moderate residual varus in posterior stabilized TKA. The aim was to evaluate the efficacy of mild and moderate residual varus in total knee replacement for primary OA knee in terms of pain relief, range of motion and stability of the joint. Methods: 30 total knee replacements were performed. All patients were examined pre- and post-operatively using the knee society clinical and functional score. The average pre-op KSS knee score was 38.7, with a functional score of 23.3. The most common reason for TKR was osteoarthritis. The follow-up time ranged from 6 to 12 months.Results: By the knee society clinical, functional score method, 96.6% of our patients received an outstanding assessment after scoring 80 points or higher. The mean post-operative KSS knee score is 86.57, and the knee society functional score is 92. 92% of patients had little/no pain after surgery, and walking ability increased and was unlimited in 80% of patients.Conclusions: After a short term follow up of 1 year in a research population of 30 with pre-operative osteo arthritis of the knee, with post-operative mild to moderate varus alignment showed better clinical results

Propositional Dynamic Logic with Converse and Repeat for Message-Passing Systems

The model checking problem for propositional dynamic logic (PDL) over message sequence charts (MSCs) and communicating finite state machines (CFMs) asks, given a channel bound $B$, a PDL formula $\varphi$ and a CFM $\mathcal{C}$, whether every existentially $B$-bounded MSC $M$ accepted by $\mathcal{C}$ satisfies $\varphi$. Recently, it was shown that this problem is PSPACE-complete. In the present work, we consider CRPDL over MSCs which is PDL equipped with the operators converse and repeat. The former enables one to walk back and forth within an MSC using a single path expression whereas the latter allows to express that a path expression can be repeated infinitely often. To solve the model checking problem for this logic, we define message sequence chart automata (MSCAs) which are multi-way alternating parity automata walking on MSCs. By exploiting a new concept called concatenation states, we are able to inductively construct, for every CRPDL formula $\varphi$, an MSCA precisely accepting the set of models of $\varphi$. As a result, we obtain that the model checking problem for CRPDL and CFMs is still in PSPACE

A magnetic susceptibility study of spin-state transitions in rare-earth trioxocobaltates(III)

Rare-earth trioxocobaltates(III), Ln[CoO3], with Ln=Pr, Nd, Tb, Dy, and Yb exhibit low-spin to high-spin transitions of cobalt characterised by a maximum in the Δχ−1 against temperature plots where Δχ is the cobalt contribution to the magnetic susceptibility. The susceptibility behaviour is distinct from that of La[CoO3] which shows a plateau in the χ−1-T curve accompanied by a structural transition. The temperature at which the Δχ−1-T curve shows a maximum increases with the decrease in the size of the rare-earth ion. The susceptibility behaviour of solid solutions of La1−xNdxCoO3 has been investigated to see how the behaviour characteristic of Nd[CoO3] changes to that of La[CoO3]

Managing Process Variants as an Information Resource

Many business solutions provide best practice process templates, both generic as well as for specific industry sectors. However, it is often the variance from template solutions that provide organizations with intellectual capital and competitive differentiation. In this paper, we present a modeling framework that is conducive to constrained variance, by supporting user driven process adaptations. The focus of the paper is on providing a means of utilizing the adaptations effectively for process improvement through effective management of the process variants repository (PVR). In particular, we will provide deliberations towards a facility to provide query functionality for PVR that is specifically targeted for effective search and retrieval of process variants

Targeting BRCA1-BER deficient breast cancer by ATM or DNA-PKcs blockade either alone or in combination with cisplatin for personalized therapy

BRCA1, a key factor in homologous recombination repair may also regulate base excision repair (BER). Targeting BRCA1-BER deficient cells by blockade of ATM and DNA-PKcs could be a promising strategy in breast cancer. We investigated BRCA1, XRCC1 and pol β protein expression in two cohorts (n=1602 sporadic and n=50 germ-line BRCA1 mutated) and mRNA expression in two cohorts (n=1952 and n=249). Artificial neural network analysis for BRCA1-DNA repair interacting genes was conducted in 249 tumours. Pre-clinically, BRCA1 proficient and deficient cells were DNA repair expression profiled and evaluated for synthetic lethality using ATM and DNA-PKcs inhibitors either alone or in combination with cisplatin. In human tumours, BRCA1 negativity was strongly associated with low XRCC1, and low pol β at mRNA and protein levels (p<0.0001). In patients with BRCA1 negative tumours, low XRCC1 or low pol β expression was significantly associated with poor survival in univariate and multivariate analysis compared to high XRCC1 or high pol β expressing BRCA1 negative tumours (ps<0.05). Pre-clinically, BRCA1 negative cancer cells exhibit low mRNA and low protein expression of XRCC1 and pol β. BRCA1-BER deficient cells were sensitive to ATM and DNA-PKcs inhibitor treatment either alone or in combination with cisplatin and synthetic lethality was evidenced by DNA double strand breaks accumulation, cell cycle arrest and apoptosis. We conclude that XRCC1 and pol β expression status in BRCA1 negative tumours may have prognostic significance. BRCA1-BER deficient cells could be targeted by ATM or DNA-PKcs inhibitors for personalized therapy

A prospective comparative study of functional outcome of distal extra articular tibia fracture fixed with intramedullary nail versus locking compression plate

Background: Distal tibia fractures are one of the most common long bone fractures and their management presents with a series of problems due to the soft tissue surroundings and even more at risk due to their proximity to ankle joint. In our paper we showed functional outcome of distal extra articular tibia fracture while comparing its management between intramedullary nailing and locking compression plate.Methods: There were 40 patients from November 2019 to November 2020 with distal extra articular tibia fracture. Patients were divided into 2 groups, first group included 20 patients managed with intramedullary nail and the second group included 20 patients managed with locking compression plate. Patients were followed preoperatively, intraoperatively and postoperatively for functional outcome and assessed clinically using AOFAS score and radiologically using X-ray.Results: Out of the 40 cases treated in this manner, all cases were available for the follow up for a period of 1 year. Overall results by 1 year follow up showed excellent in 7 cases (35%) good in 13 cases (65%) in nailing group and in plating group showed excellent in 4 cases (20%), good in 12 cases (60%), fair in 3 cases (15%) and poor in 1 case (5%).Conclusions: All fractures united well. Complications were encountered in 4 patients, 2 patients had superficial wound infections,1 patient had deep infection and another had persistent ankle pain in plating group and 2 patients had superficial wound infection in nailing group. No cases showed malunion or nonunion in both plating as well as nailing group

Distributed Synthesis in Continuous Time

We introduce a formalism modelling communication of distributed agents strictly in continuous-time. Within this framework, we study the problem of synthesising local strategies for individual agents such that a specified set of goal states is reached, or reached with at least a given probability. The flow of time is modelled explicitly based on continuous-time randomness, with two natural implications: First, the non-determinism stemming from interleaving disappears. Second, when we restrict to a subclass of non-urgent models, the quantitative value problem for two players can be solved in EXPTIME. Indeed, the explicit continuous time enables players to communicate their states by delaying synchronisation (which is unrestricted for non-urgent models). In general, the problems are undecidable already for two players in the quantitative case and three players in the qualitative case. The qualitative undecidability is shown by a reduction to decentralized POMDPs for which we provide the strongest (and rather surprising) undecidability result so far