Superior antibacterial surfaces using hydrophilic, poly(MPC) and poly(mOEGMA) free chains of amphiphilic block copolymer for sustainable use.

Surface modification of electrically neutral hydrophilic polymers is one of the most promising methods for preventing biofouling and biological contamination by proteins and bacteria. Surface modification of inorganic materials such as silica-based glass can render them more durable and thus help in achieving the sustainable development goals. This study reports a novel method for the simple and effective surface modification of glass surfaces with amphiphilic block copolymers possessing the silane coupling segment composed of 3-(methacryloyloxy)propyltris (trimethylsilyloxy) silane and 3-methacryloxypropyltrimethoxysilane. The ability of hydrophilic segments composed of either 2-methacryloyloxyethyl phosphorylcholine (MPC) or poly(ethylene glycol) methyl ether methacrylate (mOEGMA) to prevent bacterial adhesion was investigated. The target block copolymers were prepared by reversible addition-fragmentation chain transfer polymerization and the monomer units of the hydrophilic segments were controlled to be either 120 or 160. The polymers were modified on the substrate by dip-coating. Contact angle measurements indicated that the block copolymer with the PMPC hydrophilic segment formed a hydrophilic surface without pre-hydration, while those with the PmOEGMA hydrophilic segment-coated surface became hydrophilic upon immersion in water. The block copolymer-coated surfaces decreased S. aureus adhesion, and a significant reduction was observed with the MPC-type block copolymer. The following surface design guidelines were thus concluded: (1) the block copolymer is superior to the random copolymer and (2) increasing the hydrophilic segment length further decreases bacterial adhesion.

Machine Learning of Histopathological Images Predicts Recurrences of Resected Pancreatic Ductal Adenocarcinoma With Adjuvant Treatment.

OBJECTIVES: Pancreatic ductal adenocarcinoma is an intractable disease with frequent recurrence after resection and adjuvant therapy. The present study aimed to clarify whether artificial intelligence-assisted analysis of histopathological images can predict recurrence in patients with pancreatic ductal adenocarcinoma who underwent resection and adjuvant chemotherapy with tegafur/5-chloro-2,4-dihydroxypyridine/potassium oxonate. MATERIALS AND METHODS: Eighty-nine patients were enrolled in the study. Machine-learning algorithms were applied to 10-billion-scale pixel data of whole-slide histopathological images to generate key features using multiple deep autoencoders. Areas under the curve were calculated from receiver operating characteristic curves using a support vector machine with key features alone and by combining with clinical data (age and carbohydrate antigen 19-9 and carcinoembryonic antigen levels) for predicting recurrence. Supervised learning with pathological annotations was conducted to determine the significant features for predicting recurrence. RESULTS: Areas under the curves obtained were 0.73 (95% confidence interval, 0.59-0.87) by the histopathological data analysis and 0.84 (95% confidence interval, 0.73-0.94) by the combinatorial analysis of histopathological data and clinical data. Supervised learning model demonstrated that poor tumor differentiation was significantly associated with recurrence. CONCLUSIONS: Results indicate that machine learning with the integration of artificial intelligence-driven evaluation of histopathological images and conventional clinical data provides relevant prognostic information for patients with pancreatic ductal adenocarcinoma.

Protein quality control machinery supports primary ciliogenesis by eliminating GDP-bound Rab8-family GTPases.

The small GTPase Rab8 plays a vital role in the vesicular trafficking of cargo proteins from the trans-Golgi network to target membranes. Upon reaching its target destination, Rab8 is released from the vesicular membrane into the cytoplasm via guanosine triphosphate (GTP) hydrolysis. The fate of GDP-bound Rab8 released from the destination membranes, however, has not been investigated adequately. In this study, we found that GDP-bound Rab8 subfamily proteins are targeted for immediate degradation, and the pre-emptive quality control machinery is responsible for eliminating these proteins in a nucleotide-specific manner. We provide evidence that components of this quality control machinery have a critical role in vesicular trafficking events, including the formation of primary cilia, a process regulated by the Rab8 subfamily. These results suggest that the protein degradation machinery plays a critical role in the integrity of membrane trafficking by limiting the excessive accumulation of GDP-bound Rab8 subfamily proteins.

[Mucinous Cystadenocarcinoma with a Sarcomatous Component Arising from the Sigmoid Mesocolon-A Case Report].

A 53‒year‒old female was referred to our hospital for abdominal pain. A cystic tumor evolving since 12 years, which was suspected of being a lymphocyst, was detected in her left lower abdomen. Computed tomography(CT)revealed the cystic tumor with enhanced 80 mm enlarged regions. Regarding the laboratory data, inflammatory parameters and tumor markers such as CA19‒9, CEA, and CA125 were elevated. Mucinous cystadenocarcinoma was highly suspected and a surgery was performed. Laparotomy showed that the tumor was located in the sigmoid mesocolon and there were multiple peritoneal disseminations. The tumor could not be separated from the sigmoid colon; therefore, tumor resection with partial sigmoidectomy was performed. The resected specimens showed mucus and solid lesions in the cystic tumor. The pathological findings revealed that the cystic tumor from the sigmoid mesocolon was a mucinous cystadenocarcinoma with large spindle‒ shaped atypical cells, which were considered to have undergone sarcomatous changes. No cases of mucinous cystadenocarcinoma with sarcoma arising from the sigmoid mesocolon have been previously reported. The prognosis of mucinous cystic neoplasm with sarcoma is suspected to be very poor, and the accumulation of such cases could help in improving their treatment.

Malignant rhabdoid tumours of the small intestine with multiple organ involvement: Case report.

INTRODUCTION AND IMPORTANCE: Malignant rhabdoid tumours (MRTs) were first described as an infrequent variant of Wilms' tumour and have been reported in several organs. The small intestine is a rare site for MRTs. CASE PRESENTATION: A 70-year-old man presented with appetite loss and melena. Haemorrhagic small intestinal tumours, swollen mesenteric and paraaortic lymph nodes, a tumour in the left kidney, and multiple tumours in the lung were found. He underwent partial resection of two haemorrhagic small intestinal tumours classified as MRTs based on the results of a pathological examination. However, melena appeared again on postoperative day 6. We performed another operation and resected approximately 180 cm of the small intestine that contained multiple tumours. All lesions were classified as MRTs. Unfortunately, melena appeared again 4 days after the second operation. He did not want invasive therapy and died from massive melena 2 months after the initial surgery. CLINICAL DISCUSSION: MRTs of the small intestine are uncommon and have an extremely poor prognosis. Although curative resection is an important treatment, cases of metastasis at diagnosis and postoperative early recurrence have been observed, as was the case for the patient described herein. In these cases, effective systemic therapy is necessary. Recently, tumour suppressor genes were shown to be involved in the occurrence of MRT, and new therapies for MRT have been studied. CONCLUSION: We herein conclude effective systemic therapy is necessary for MRTs with multiple organ involvement. The development of new drugs for this disease is ongoing.

[Two Cases of Locally Advanced Colorectal Cancer Involving Pathological Complete Response after Chemotherapy].

We report 2 cases of locally advanced colorectal cancer in which complete response(CR)was achieved after chemotherapy. Case 1 involved a 71-year-old male diagnosed with rectal cancer invading the bladder. Chemotherapy with SOX plus bevacizumab and IRIS plus bevacizumab was administered for rectal cancer. Post-chemotherapy, the disease showed clinical CR(cCR)according to the Response Evaluation Criteria in Solid Tumors(RECIST). A laparoscopic abdominoperineal resection was then performed, with pathological findings showing no viable cancer cells. Eleven months postoperatively, the patient remains alive without disease recurrence. Case 2 involved a 54-year-old female diagnosed with a peritoneal abscess resulting from perforated sigmoid colon cancer. She received chemotherapy with SOX plus bevacizumab. Post-chemotherapy, the disease showed cCR according to the RECIST. A sigmoidectomy was performed, with pathological findings showing no viable cancer cells. Ten months postoperatively, the patient remains alive without disease recurrence. We believe that neoadjuvant chemotherapy is a feasible treatment option for locally advanced colorectal cancer.

Nuclear accumulation of ZFP36L1 is cell cycle-dependent and determined by a C-terminal serine-rich cluster.

ZFP36L1 is an RNA-binding protein responsible for mRNA decay in the cytoplasm. ZFP36L1 has also been suggested as a nuclear-cytoplasmic shuttling protein because it contains a potential nuclear localization signal and a nuclear export signal. However, it remains unclear how the nuclear localization of ZFP36L1 is controlled. In this study, we provide evidence that the nuclear accumulation of ZFP36L1 protein is modulated in a cell cycle-dependent manner. ZFP36L1 protein accumulation in fractionated nuclei was particularly prominent in cells arrested at G1-/S-phase boundary, while it was downregulated in S-phase cells, and eventually disappeared in G2-phase nuclei. Moreover, forced nuclear targeting of ZFP36L1 revealed marked downregulation of this protein in S- and G2-phase cells, suggesting that ZFP36L1 can be eliminated in the nucleus. The C-terminal serine-rich cluster of ZFP36L1 is critical for the regulation of its nuclear accumulation because truncation of this probable disordered region enhanced the nuclear localization of ZFP36L1, increased its stability and abolished its cell cycle-dependent fluctuations. These findings provide the first hints to the question of how ZFP36L1 nuclear accumulation is controlled during the course of the cell cycle.

[Two Cases of Resectable Liver Metastasis from Colorectal Cancer with Pathological Complete Response after Neoadjuvant Chemotherapy].

A 57-year-old male, who had received a laparoscopic low anterior resection for rectal cancer 12 months ago, was diagnosed a resectable liver metastasis from rectal cancer by computed tomography(CT). Neoadjuvant chemotherapy with mFOLFOX6 plus bevacizumab and FOLFIRI plus bevacizumab was performed for liver metastasis. After neoadjuvant chemotherapy, partial response(PR)was proved on the Response Evaluation Criteria in Solid Tumors(RECIST)and partial resection of the liver was conducted. Pathological findings showed no viable cancer cells. He is alive without recurrence 5 years after the surgery. A 70-year-old female, who had received a laparoscopic high anterior resection for rectal cancer 17 months ago, was diagnosed a resectable liver metastasis from rectal cancer by CT. SOX plus bevacizumab was performed for liver metastasis. After neoadjuvant chemotherapy, PR was proved on the RECIST and right hepatic lobectomy was performed. Pathological findings showed no viable cancer cells and she is alive without recurrence 4 years after the surgery. We expected neoadjuvant chemotherapy for resectable liver metastasis might be an option of treatment.

Reversing the Handedness of Self-Assembled Porous Molecular Networks through the Number of Identical Chiral Centres.

Scanning tunnelling microscope observations at the 1-phenyloctane/graphite interface reveal how chiral structural information at the molecular level is transferred and expressed structurally at the 2D supramolecular level for a porous system. The chirality of self-assembled molecular networks formed by chiral dehydrobenzo[12]annulene (cDBA) derivatives having three chiral chains and three achiral chains, alternatingly, is compared with those of cDBAs having six chiral chains reported previously. While for all cDBAs homochiral surfaces are formed, their handedness is not simply a reflection of the absolute configuration of the stereogenic centres. Both the number of stereogenic centres as well as the length of the achiral chains determine the supramolecular handedness, providing a deep insight into the supramolecular chirality induction mechanisms at play. Moreover, these cDBAs act to induce chirality in porous networks formed by achiral DBAs.

Novel phosphorelay-dependent control of ZFP36L1 protein during the cell cycle.

The ZFP36 family is a prototypical member of a highly conserved group of proteins with CCCH-type RNA-binding domains, whose functional role and regulatory mechanism in mitotic cells remain obscure. In this study, we provide the first evidence that ZFP36L1 phosphorylation is modulated in a cell cycle-dependent manner. The C-terminal region of ZFP36L1 is critical for its cell cycle-dependent phosphorylation of this protein. We also suggest that the phosphorelay-dependent regulation of ZFP36L1 influences mitotic spindle organization. Thus, our data demonstrate a new class of regulatory mechanism for CCCH-type zinc-finger proteins in cell cycle control.

ZFP36L2 is a cell cycle-regulated CCCH protein necessary for DNA lesion-induced S-phase arrest.

ZFP36L2 promotes the destruction of AU-rich element-containing transcripts, while its regulation and functional significance in cell cycle control are scarcely identified. We show that ZFP36L2 is a cell cycle-regulated CCCH protein, the abundance of which is regulated post-translationally at the respective stages of the cell cycle. Indeed, ZFP36L2 protein was eliminated after release from M phase, and ZYG11B-based E3 ligase plays a role in its polyubiquitination in interphase. Although ZFP36L2 is dispensable for normal cell cycle progression, we found that endogenous ZFP36L2 played a key role in cisplatin-induced S-phase arrest, a process in which the suppression of G1/S cyclins is necessary. The accumulation of ZFP36L2 was stimulated under DNA replication stresses and altered interactions with a subset of RNA-binding proteins. Notably, silencing endogenous ZFP36L2 led to impaired cell viability in the presence of cisplatin-induced DNA lesions. Thus, we propose that ZFP36L2 is a key protein that controls S-phase progression in the case of genome instability.

Predictors of Recurrence in Vogt-Koyanagi-Harada Disease.

PURPOSE: Normally, Vogt-Koyanagi-Harada (VKH) disease has a good prognosis with adequate treatment. However, VKH disease recurs more frequently if diagnosis is delayed or treatment is inadequate. As soon as VKH disease recurs, inflammation is harder to control and the prognosis worsens. Our objective was to study predictors of recurrence in patients with VKH disease. DESIGN: Retrospective case series. PARTICIPANTS: Forty-one eyes of 41 patients (25 women, 16 men) were included in this study. Patients with recurrent attacks of inflammation were classified as recurrent, whereas patients needing only steroid treatment, without any recurrent attacks, were classified as nonrecurrent. METHODS: Descriptive and bivariate analyses were used to characterize disease and outcomes. A blood-flow analysis was performed with laser speckle flowgraphy on days 0, 14, 30, and 60. Choroidal thickness was measured with swept-source OCT, using a 12-radial scan protocol, on the same day as mean blur rate (MBR) measurement. Flare in the anterior chamber also was measured on the same day, using a flare cell meter. MAIN OUTCOME MEASURES: Prevalence of each type of disease pattern and flare, MBR, and thickness of the choroidal layers. RESULTS: The recurrent group initially had lower visual acuity (VA) and higher flare than the nonrecurrent group, but these parameters improved over time and were similar in the groups on days 14, 30, and 60. However, on these days, MBR was significantly lower in the recurrent group than in the nonrecurrent group. Choroidal thickness was not significantly different in the 2 groups at any time point. CONCLUSIONS: We found that patients with recurrent VKH disease had lower VA, higher initial flare number, and a lower response of MBR to treatment than patients with nonrecurrent VKH disease. Thus, VA and flare number during the initial phase, as well as the MBR response to treatment, may be useful in determining the prognosis for VKH disease and choosing therapeutic options.

Elimination of a signal sequence-uncleaved form of defective HLA protein through BAG6.

A portion of newly synthesized transmembrane domain proteins tend to fail to assemble correctly in the lumen of the endoplasmic reticulum, thus resulting in the production of a signal sequence-uncleaved form of the defective species. Although the efficient degradation of these mistargeted polypeptides is crucial, the molecular mechanism of their elimination pathway has not been adequately characterized. In this study, we focused on one such cryptic portion of a defective transmembrane domain protein, HLA-A, and show that a part of HLA-A is produced as a signal sequence-uncleaved labile species that is immediately targeted to the degradation pathway. We found that both BAG6 and proteasomes are indispensable for elimination of mislocalized HLA-A species. Furthermore, defective HLA-A is subjected to BAG6-dependent solubilization in the cytoplasm. These observations suggest that BAG6 acts as a critical factor for proteasome-mediated degradation of mislocalized HLA-A with a non-cleaved signal sequence at its N-terminus.

Transfer of chiral information from a chiral solvent to a two-dimensional network.

Chiral induction in self-assembled monolayers has garnered considerable attention in the recent past, not only due to its importance in chiral resolution and enantioselective heterogeneous catalysis but also because of its relevance to the origin of homochirality in life. Here, we demonstrate the emergence of homochirality in a supramolecular low-density network formed by achiral molecules at the interface of a chiral solvent and an atomically-flat achiral substrate. We focus on the impact of structure and functionality of the adsorbate and the chiral solvent on the chiral induction efficiency in self-assembled physisorbed monolayers, as revealed by scanning tunneling microscopy. Different induction mechanisms are proposed and evaluated, with the assistance of advanced molecular modeling simulations.

Dynamic control over supramolecular handedness by selecting chiral induction pathways at the solution-solid interface.

A dominant theme within the research on two-dimensional chirality is the sergeant-soldiers principle, wherein a small fraction of chiral molecules (sergeants) is used to skew the handedness of achiral molecules (soldiers) to generate a homochiral surface. Here, we have combined the sergeant-soldiers principle with temperature-dependent molecular self-assembly to unravel a peculiar chiral amplification mechanism at the solution-solid interface in which, depending on the concentration of a sergeant-soldiers solution, the majority handedness of the system can either be amplified or entirely reversed after an annealing step, furnishing a homochiral surface. Two discrete pathways that affect different stages of two-dimensional crystal growth are invoked for rationalizing this phenomenon and we present a set of experiments where the access to each pathway can be precisely controlled. These results demonstrate that a detailed understanding of subtle intermolecular and interfacial interactions can be used to induce drastic changes in the handedness of a supramolecular network.

On the stability of surface-confined nanoporous molecular networks.

Self-assembly of molecular building blocks into two-dimensional nanoporous networks has been a topic of broad interest for many years. However, various factors govern the specific outcome of the self-assembly process, and understanding and controlling these are key to successful creation. In this work, the self-assembly of two alkylated dehydrobenzo[12]annulene building blocks was compared at the liquid-solid interface. It turned out that only a small chemical modification within the building blocks resulted in enhanced domain sizes and stability of the porous packing relative to the dense linear packing. Applying a thermodynamic model for phase transition revealed some key aspects for network formation.

Towards enantioselective adsorption in surface-confined nanoporous systems.

The adsorption of chiral molecules in surface-confined chiral porous networks shows pronounced selectivity, as a result of complementary host-guest interactions.

Harnessing by a diacetylene unit: a molecular design for porous two-dimensional network formation at the liquid/solid interface.

Through the precise molecular design for alkoxy dehydro[12]annulene derivatives harnessed by a diacetylene unit in each alkyl chain, porous two-dimensional networks with giant pores were formed at the liquid/graphite interface.