Unusual Canal Morphology in Mandibular Premolars With Two Distal and One Mesial Canal: A Case Series.

Mandibular premolars exhibit intricate and diverse root canal anatomy, presenting substantial challenges in endodontic treatment. Uncommon variations, such as the presence of three canals, demand meticulous diagnostic and therapeutic approaches to mitigate the risk of overlooking canals and subsequent treatment failure. This case report highlights three cases of mandibular premolars exhibiting a rare root canal configuration with one mesial and two distal canals, successfully managed using cone beam computed tomography (CBCT) for accurate diagnosis and ultrasonic activation for disinfection.

Poly (ADP-Ribose) Polymerase Inhibitor Olaparib-Resistant -Mutant Ovarian Cancer Cells Demonstrate Differential Sensitivity to PARP Inhibitor Rechallenge.

Poly (ADP-ribose) polymerase inhibitors (PARPis) show cytotoxicity in homologous recombination deficiency (HRD) seen in -mutant ovarian cancer (OvCa). Despite initial responses, resistance often develops. The reintroduction of different PARPis, such as niraparib or rucaparib, has shown some clinical activity in mutation-associated OvCa patients with prior olaparib treatment, yet the underlying mechanisms remain unclear.

The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial.

The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR).

AKT1 interacts with DHX9 to Mitigate R Loop-Induced Replication Stress in Ovarian Cancer.

Unlabelled: PARP inhibitor (PARPi)-resistant BRCA-mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Here, we performed a quantitative high-throughput drug combination screen that identified the combination of an ATR inhibitor (ATRi) and an AKT inhibitor (AKTi) as an effective treatment strategy for both PARPi-sensitive and PARPi-resistant BRCAm HGSOC. The ATRi and AKTi combination induced DNA damage and R loop-mediated replication stress (RS).

Distinct roles of treatment schemes and BRCA2 on the restoration of homologous recombination DNA repair and PARP inhibitor resistance in ovarian cancer.

Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a major advance in ovarian cancer, now as a treatment and as a maintenance therapy in the upfront and recurrent settings. However, patients often develop resistance to PARPis, underlining the importance of dissecting resistance mechanisms. Here, we report different dosing/timing schemes of PARPi treatment in BRCA2-mutant PEO1 cells, resulting in the simultaneous development of distinct resistance mechanisms.

Chest wall reconstruction: success of a team approach-a 12-year experience from a tertiary care institution.

Background: The thoracic cavity was considered as a forbidden area in the past and anyone attempting to meddle with it was expected to be doomed. But the past several decades have seen a marked improvement in the management and reconstruction of complex chest wall defects. This study was undertaken to review our experience in chest wall reconstruction during the past 12 years and to stress upon the importance of a multidisciplinary team approach to this complex problem.

Targeting the PI3K/mTOR Pathway Augments CHK1 Inhibitor-Induced Replication Stress and Antitumor Activity in High-Grade Serous Ovarian Cancer.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in industrialized countries and has limited treatment options. Targeting ataxia-telangiectasia and Rad3-related/cell-cycle checkpoint kinase 1 (CHK1)-mediated S-phase and G-M-phase cell-cycle checkpoints has been a promising therapeutic strategy in HGSOC. To improve the efficacy of CHK1 inhibitor (CHK1i), we conducted a high-throughput drug combination screening in HGSOC cells.

Resistance to the CHK1 inhibitor prexasertib involves functionally distinct CHK1 activities in BRCA wild-type ovarian cancer.

High grade serous ovarian cancer (HGSOC) is a fatal gynecologic malignancy in the U.S. with limited treatment options.

A Phase II Single Arm Pilot Study of the CHK1 Inhibitor Prexasertib (LY2606368) in BRCA Wild-Type, Advanced Triple-Negative Breast Cancer.

Lessons Learned: Monotherapy with prexasertib demonstrated modest activity in BRCA wild-type, recurrent triple-negative breast cancer, highlighting the unmet need for combination treatment strategies. Neutropenia, anemia, and thrombocytopenia are common with the use of prexasertib but are manageable with supportive care measures. Prophylactic use of granulocyte colony stimulating factor should be considered to avoid dose reductions or treatment delays.

Combination of PARP Inhibitor Olaparib, and PD-L1 Inhibitor Durvalumab, in Recurrent Ovarian Cancer: a Proof-of-Concept Phase II Study.

Purpose: Preclinical studies suggest PARP inhibition (PARPi) induces immunostimulatory micromilieu in ovarian cancer thus complementing activity of immune checkpoint blockade. We conducted a phase II trial of PARPi olaparib and anti-PD-L1 durvalumab and collected paired fresh core biopsies and blood samples to test this hypothesis.

Patients And Methods: In a single-center, proof-of-concept phase II study, we enrolled women aged ≥18 with recurrent ovarian cancer.

Patients with BRCA mutated ovarian cancer may have fewer circulating MDSC and more peripheral CD8 T cells compared with women with BRCA wild-type disease during the early disease course.

Immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are associated with immunologic tolerance and poor prognosis in ovarian cancer (OvCa). We hypothesized that women with germline BRCA1 and BRCA2 mutation-associated (gBRCAm) OvCa would have fewer circulating immunosuppressive immune cells compared to those with BRCA wild-type (BRCAwt) disease during their early disease course (<5 years post-diagnosis) where gBRCAm is a favorable prognostic factor. We collected and viably froze peripheral blood mononuclear cells (PBMCs) from patients with recurrent OvCa olaparib clinical trials (NCT01445418/NCT01237067).

"Not all bullae are synonymous with COPD"-a rare congenital anomaly described.

Hyperlucent areas with thin walls and absent vascular markings in chest X ray are described as radiological findings of a bullae. We present the case of an adult male referred for coronary revascularisation and bullectomy in the right lung. A non-smoker, without any significant past medical history, made us think of bronchial atresia.

Should all tubercular cavities be left alone? Lessons from a heart transplant.

Fungal infection after solid organ transplantation poses a diagnostic and therapeutic challenge. We present the case of a 50-year-old man who underwent orthotopic heart transplantation for dilated cardiomyopathy with a history of treated pulmonary tuberculosis 10 years pre-transplant. One year post-transplantation, he was admitted with recurrent productive cough and was evaluated to have intracavitory aspergillosis of the lung.

Lifestyle practices, health problems, and quality of life after coronary artery bypass grafting.

Introduction: Severe coronary artery disease continues to be a major health problem in India, and coronary artery bypass grafting (CABG) is the accepted modality of treatment. Post-operative long-term quality of life depends on the healthy lifestyle practices and appropriate control of risk factors. We tried to bring out the patient awareness and their practices after the surgery and their implications on their quality of life (QOL).

Brucellosis After Cardiac Transplantation.

Brucellosis is being increasingly recognized after solid organ transplantation but has not been reported after orthotopic heart transplantation. We present the case of a 51-year-old farmer who underwent orthotopic heart transplantation and was readmitted after 3 months in a severely immunosuppressed state with significant nonspecific complaints. He posed a diagnostic and management dilemma to all disciplines, but finally turned out to be harboring Brucella infection.

Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: a first-in-class proof-of-concept phase 2 study.

Background: High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle checkpoint kinase 1 and 2 inhibitor, would be active in BRCA wild-type disease.

Methods: In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma.

Prexasertib, a cell cycle checkpoint kinases 1 and 2 inhibitor, increases toxicity of PARP inhibition by preventing Rad51 foci formation in wild type high-grade serous ovarian cancer.

PARP inhibitors (PARPi) have been effective in high-grade serous ovarian cancer (HGSOC), although clinical activity is limited against wild type HGSOC. The nearly universal loss of normal p53 regulation in HGSOCs causes dysfunction in the G1/S checkpoint, making tumor cells reliant on Chk1-mediated G2/M cell cycle arrest for DNA repair. Therefore, Chk1 is a reasonable target for a combination strategy with PARPi in treating wild type HGSOC.

CD28 Promotes Plasma Cell Survival, Sustained Antibody Responses, and BLIMP-1 Upregulation through Its Distal PYAP Proline Motif.

In health, long-lived plasma cells (LLPC) are essential for durable protective humoral immunity, and, conversely, in disease are a major source of pathogenic Abs in autoimmunity, graft rejection, and allergy. However, the molecular basis for their longevity is largely unknown. We have recently found that CD28 signaling in plasma cells (PC) is essential for sustaining Ab titers, by supporting the survival of LLPC, but not short-lived PC (SLPC).

CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma.

Chemotherapeutic resistance remains a significant hurdle in the treatment of multiple myeloma (MM) and is significantly mediated by interactions between MM cells and stromal cells of the bone marrow microenvironment. Despite the importance of these interactions, the specific molecules and downstream signaling components involved remain incompletely understood. We have previously shown that the prototypic T-cell costimulatory receptor CD28, which is also expressed on MM cells, is a key mediator of MM survival and apoptotic resistance.

Novel regulation of CD80/CD86-induced phosphatidylinositol 3-kinase signaling by NOTCH1 protein in interleukin-6 and indoleamine 2,3-dioxygenase production by dendritic cells.

Dendritic cells (DC) play a critical role in modulating antigen-specific immune responses elicited by T cells via engagement of the prototypic T cell costimulatory receptor CD28 by the cognate ligands CD80/CD86, expressed on DC. Although CD28 signaling in T cell activation has been well characterized, it has only recently been shown that CD80/CD86, which have no demonstrated binding domains for signaling proteins in their cytoplasmic tails, nonetheless also transduce signals to the DC. Functionally, CD80/CD86 engagement results in DC production of the pro-inflammatory cytokine IL-6, which is necessary for full T cell activation.

Under one roof: The bone marrow survival niche for multiple myeloma and normal plasma cells.

Our recently published data demonstrate significant similarities between normal and malignant plasma cells in the cellular and molecular interactions that support their survival in the bone marrow microenvironment, and suggest that the biology of multiple myeloma may largely reflect that of their normal counterparts.