Mutations underlie all cancers, and their identification and study are the foundation of cancer biology. We describe what we believe to be a novel approach to mutagenesis and cancer studies based on the DNA polymerase ε (POLE) ultramutator phenotype recently described in human cancers, in which a single amino acid substitution (most commonly P286R) in the proofreading domain results in error-prone DNA replication. We engineered a conditional PoleP286R allele in mice. PoleP286R/+ embryonic fibroblasts exhibited a striking mutator phenotype and immortalized more efficiently. PoleP286R/+ mice were born at Mendelian ratios but rapidly developed lethal cancers of diverse lineages, yielding the most cancer-prone monoallelic model described to date, to our knowledge. Comprehensive whole-genome sequencing analyses showed that the cancers were driven by high base substitution rates in the range of human cancers, overcoming a major limitation of previous murine cancer models. These data establish polymerase-mediated ultramutagenesis as an efficient in vivo approach for the generation of diverse animal cancer models that recapitulate the high mutational loads inherent to human cancers.

Potassium titanyl phosphate KTiOPO4 (KTP) crystals with periodical ferroelectric domain structures are one of the most promising materials for nonlinear optics, in which the main types of nonlinear optical interactions have been demonstrated. Despite the crucial importance of the in situ visualization of domain structure kinetics for creation of high quality periodical domain gratings, there are only a few works concerning KTP. We present the results of in situ visualization of domain kinetics in KTP with the time resolution down to 12.5 μs and simultaneous recording of the switching current data. The wide range of wall velocities with two orders of magnitude difference was observed for switching in a uniform electric field. The kinetic maps allowed analyzing the spatial distribution of wall motion velocities and classifying the walls by velocity ranges. The distinguished slow, fast, and superfast types of domain walls differed by their orientation. It was shown that the fast and slow domain walls provided the smooth input to the switching current, whereas the short-lived superfast walls resulted in short current peaks. The mobility and the threshold fields for all types of domain walls were estimated. The revealed increase in the wall velocity with deviation from low-index crystallographic planes for slow and fast walls was considered in terms of determined step generation and anisotropic kink motion. The obtained results are important for further development of domain engineering in KTP required for creation of high power, reliable, and effective coherent light sources.

Prompt and accurate diagnosis of Nocardia skin infections is important in immunocompromised hosts, especially transplant patients. The sporotrichoid form, which is otherwise known as the lymphocutaneous form of Nocardia skin involvement, can mimic other conditions, including those caused by fungi, mycobacteria, spirochetes, parasites and other bacteria. Delayed or inaccurate diagnosis and treatment of Nocardia skin infections in transplant patients could lead to dissemination of disease and other poor outcomes. Nocardia brasiliensis is a rare cause of lymphocutaneous nocardiosis in solid organ transplant patients with only two other cases reported to our knowledge. This case describes a middle-aged man, who presented 16 years post kidney transplant. He developed a sporotrichoid lesion on his upper extremity one week after gardening. Ultrasound showed a 35-cm abscess tract on his forearm, which was subsequently drained. Nocardia brasiliensis was isolated from pus culture and he was treated successfully with amoxicillin/clavulanate for 6 months. A review of the relevant literature is included.

TP53 is the most frequently mutated gene in head and neck squamous cell carcinoma (HNSCC). Patients with HPV-negative TP53 mutant HNSCC have the worst prognosis, necessitating additional agents for treatment. Since mutant p53 causes sustained activation of the PI3K/AKT/mTOR signaling pathway, we investigated the effect of rapalogs RAD001 and CCI-779 on HPV-negative mutTP53 HNSCC cell lines and xenografts. Rapalogs significantly reduced cell viability and colony formation. Interestingly, rapalogs-induced autophagy with no effect on apoptosis.Pretreatment with autophagy inhibitors, 3-methyladenine (3-MA) and ULK-101 rescued the cell viability by inhibiting rapalog-induced autophagy, suggesting that both RAD001 and CCI-779 induce non-apoptotic autophagy-dependent cell death (ADCD). Moreover, rapalogs upregulated the levels of ULK1 and pULK1 S555 with concomitant downregulation of the mTORC1 pathway. However, pretreatment of cells with rapalogs prevented the ULK-101-mediated inhibition of ULK1 to sustained autophagy, suggesting that rapalogs induce ADCD through the activation of ULK1.To further translate our in vitro studies, we investigated the effect of RAD001 in HPV-negative mutTP53 (HN31 and FaDu) tumor cell xenograft model in nude mice.Mice treated with RAD001 exhibited a significant tumor volume reduction without induction of apoptosis, and with a concomitant increase in autophagy. Further, treatment with RAD001 was associated with a considerable increase in pULK1 S555 and ULK1 levels through the inhibition of mTORC1. 3-MA reversed the effect of RAD001 on FaDu tumor growth suggesting that RAD001 promotes ACDC in HPVnegative mutTP53 xenograft. This is the first report demonstrating that rapalogs promote non-apoptotic ADCD in HPV-negative mutTP53 HNSCC via the ULK1 pathway. Further studies are required to establish the promising role of rapalogs in preventing the regrowth of HPV-negative mutTP53 HNSCC.

This study proposes a new hepta‐band antenna that consists of an inductive ground plane and slots loaded patch for the multiband body‐worn scenario. The phase distribution is optimised by considering a 7 × 7 array of periodic square patches on the metallic ground‐backed substrate in such a way that resonant modes of patch slots interact with the resonant modes of meta‐resonators of inductive ground to achieve hepta‐band behaviour with desired radiation characteristics. Each unit cell corresponds to a phase shift of 3.6° out of available phase distribution of 180°. The seven bands are targeted at 1.8, 2.45, 2.96, 3.5, 3.8, 4.2, and 4.5 GHz which supports GSM (1.8 GHz), WLAN (2.4 GHz), LTE (2.5 GHz), Wi‐MAX (3.5 GHz), sub‐6 GHz 5G band (3.4‐4.2 GHz), navigation (2.96 GHz), and satellite (4.5 GHz) applications. It is also demonstrated that an inductive ground plane can be used to get reduced SAR and increased FBR, making antenna useful for wearable applications. The proposed antenna has a patch size of 28.84 × 28.84 mm upon a 0.4 mm thick substrate of permittivity 4.3. Inductive ground is made of via‐free periodic square patches each of size 5 × 5 mm on the 2.6 mm thick metallic ground‐backed substrate.

Healthcare waste management (HCWM) options are inconsistent in Bangladesh. One of the first critical steps in the process of developing a reliable waste management plan requires a comprehensive understanding of the quantities and characteristics of the waste that needs to be managed. This study took into consideration both the quantity and quality of the generated waste to determine the generation rates and physical properties of healthcare waste (HCW) in Chittagong Medical College Hospital (CMCH) and also to estimate the amount of infectious and non-infectious waste generated in different wards. CMCH, the second largest hospital in Bangladesh, comprises 34 wards, 12 of which were selected randomly. Waste materials were collected from these wards and then segregated and weighed. Waste generation per day was found to be 73.22 kg/ward, 1.28 kg/bed and 0.57 kg/patient. A total of 2490 kg of HCW was produced each day in CMCH (37% being infectious and the rest being non-infectious waste). Infectious waste was 27.07 kg per ward, 0.47 kg per bed and 0.21 kg per patient and the non-infectious waste was 46.15 kg per ward, 0.81 kg per bed and 0.36 kg per patient per day. HCW comprised eight categories of waste materials with vegetable/food waste being the largest component (50.21%) and varied significantly (P < 0.05) among the 12 different wards studied. The greatest amount of HCW was recorded (154 kg) in Orthopaedics followed by 96.66 kg in the Medicine Unit-3 and the smallest amount was recorded in Casualty (8.79 kg). The amount of HCW was positively correlated with the number of occupied beds (rxy = 0.79, P < 0.01). There is no structured form of medical waste treatment in CMCH and most waste materials are dumped in open areas for natural degradation or re-sold by scavengers. It is essential to develop a national policy and implement a comprehensive action plan for HCWM that will provide environmentally sound technological measures to improve HCWM in Bangladesh.

Aim. To assess the effect of treating chronic hepatitis C virus (HCV) infection with direct acting antiviral drugs (DAAs) on glycemic control in patients with concomitant diabetes mellitus (DM). Methods. We performed a retrospective case-control study in a viral hepatitis ambulatory clinic in Shreveport, Louisiana, during the period 11/01/2014 to 12/31/2017. All the clinic patient ages 18 years and above with treatment-naïve/biopsy-proven chronic hepatitis C and DM (hemoglobin A1C level≥6.5%) who were eligible for treatment were included in the study. Of 118 such patients, 59 were treated with oral DAAs for 8-12 weeks with the goal of achieving a sustained virologic response (SVR). A control group of 59 patients did not receive treatment for their hepatitis C and was followed in the clinic. Patients in the control group did not receive treatment either due to insurance issues or refusal of hepatitis C treatment. Results. Fifty-five of the 59 patients treated with DAAs (93%) achieved a SVR. Six months after treatment completion, their mean±SEM HbA1C level had decreased by 1.1±0.03% (P<0.0001). Four of the 59 patients treated with DAAs did not achieve a SVR. Their mean HbA1C 6 months after treatment completion had increased by 0.8±0.2%. Furthermore, there was no improvement in HbA1C levels over time in the untreated group (mean HbA1C increase, 0.2±0.05%; P<0.0001 vs. the treatment group, which had a mean HbA1C decrease of 0.9±0.2%). Conclusion. This controlled study demonstrated that treatment of chronic hepatitis C with DAAs results in statistically significant and meaningful reductions in hemoglobin A1C levels in patients with coexisting diabetic mellitus if a SVR is achieved.

Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived invasive and metastatic tumor of the skin and is the second-most commonly diagnosed form of skin cancer (16%) striking 200,000 Americans annually. Increased exposure to Ultraviolet-B (UVB) from solar radiation as a result of the depletion of the ozone layer and the widespread use of tanning beds are the primary reasons for the increased incidence of cSCC. Novel mechanism-based therapeutics are needed to prevent UVB-induced cSCC. Chemokines are a group of small chemotactic cytokines that can exert extensive and complex effects on cancer via interaction with their receptors. Chemokine (C-X-C motif) ligand 17 (CXCL17) is the latest member of the chemokine family, and recent studies have identified both a causative and suppressive role of CXCL17 and its cognate receptor GPR35 in tumorigenesis. The purpose of this study was to determine the role of CXCL17 and GPR35 in the pathogenesis of cSCC. CXCL17 and GPR35 were significantly overexpressed in cSCC cells (SCC12A and SCC118) compared to HaCaT cells. Stimulation with CXCL17 significantly induced cSCC cell proliferation, migration, and motility suggesting an essential role in tumor growth, invasion, and metastasis. Tumor-specific overexpression of CXCL17 was detected in human cSCC and UVB-induced mouse cSCCs that further bolsters our in vitro findings. Recent studies have also identified the role of CXCL17 in tumor cell infiltration and immune invasion leading to tumor progression. In our preliminary studies, increased expression of CXCL17 in cSCC correlated with an augmented number of CD3+, CD4+ and CD8+ T-cells infiltrates. Our data suggest that CXCL17 could potentially exert differential effects based on cell types in the tumor microenvironment. Our studies underscore the importance of CXCL17/GPR35 signaling in cSCC and provide a novel target for the treatment of non-melanoma skin cancer. Citation Format: Alok R. Khandelwal, Md Maksud Alam, Tara Moore-Medlin, Hillary A. Savage, Cherie-Ann O. Nathan. Role of the CXCL17-CXCR8 (GPR35) axis in cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1969.